Indazole compounds, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation

ABSTRACT

Indazole compounds that modulate and/or inhibit cell proliferation, such as the activity of protein kinases are described. These compounds and pharmaceutical compositions containing them are capable of mediating, e.g., kinases-dependent diseases to modulate and/or inhibit unwanted cell proliferation. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds, and to methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis, by administering effective amounts of such compounds.

This application claims priority from and incorporates by reference inits entirety U.S. Provisional Application Serial No. 60/176,484 filedJan. 18, 2000.

FIELD OF THE INVENTION

This invention is directed to indazole compounds that mediate and/orinhibit cell proliferation, for example, through the inhibition of theactivity of protein kinases, such as VEGF, CHK-1, and cyclin-dependentkinases (CDKs), such as CDK1, CDK2, CDK4, and CDK6. The invention isfurther related to pharmaceutical compositions containing such compoundsand compositions, and to methods of treating cancer as well as otherdisease states associated with unwanted angiogenesis and/or cellularproliferation, by administering effective amounts of such compounds.

BACKGROUND OF THE INVENTION

Uncontrolled cell proliferation is the insignia of cancer. Cellproliferation in response to various stimuli is manifested by aderegulation of the cell division cycle, the process by which cellsmultiply and divide. Tumor cells typically have damage to the genes thatdirectly or indirectly regulate progression through the cell divisioncycle.

Hyperproliferative disease states, including cancer, are characterizedby cells rampantly winding through the cell cycle with uncontrolledvigor due to, for example, damage to the genes that directly orindirectly regulate progression through the cycle. Thus, agents thatmodulate the cell cycle, and thus hyperproliferation, could be used totreat various disease states associated with uncontrolled or unwantedcell proliferation. In addition to cancer chemotherapeutic agents, cellcycle inhibitors are also proposed as antiparasitics (See, Gray et al.,Curr. Med. Chem. 6, 859-875 (1999)) and recently demonstrated aspotential antivirals (See, Schang et al., J. Virol. 74, 2107-2120(2000)). Moreover, the applicability of antiproliferative agents may beexpanded to treating cardiovascular maladies such as artherosclerosis orrestenosis (See Braun-Dullaeus et al., Circulation, 98, 82-89 (1998)),and states of inflammation, such as arthritis (See, Taniguchi et al.,Nature Med., 5, 760-767(1999)) or psoriasis.

Mechanisms of cell proliferation are under active investigation atcellular and molecular levels. At the cellular level, de-regulation ofsignaling pathways, loss of cell cycle controls, unbridled angiogenesisor stimulation of inflammatory pathways are under scrutiny, while at themolecular level, these processes are modulated by various proteins,among which protein kinases are prominent suspects. Overall abatement ofproliferation may also result from programmed cell death, or apoptosis,which is also regulated via multiple pathways, some involvingproteolytic enzyme proteins.

Among the candidate regulatory proteins, protein kinases are a family ofenzymes that catalyze phosphorylation of the hydroxyl group of specifictyrosine, serine, or threonine residues in proteins. Typically, suchphosphorylation dramatically perturbs the function of the protein, andthus protein kinases are pivotal in the regulation of a wide variety ofcellular processes, including metabolisim, cell proliferation, celldifferentiation, and cell survival. Of the many different cellularfunctions in which the activity of protein kinases is known to berequired, some processes represent attractive targets for therapeuticintervention for certain disease states. Two examples are cell-cyclecontrol and angiogenesis, in which protein kinases play a pivotal role;these processes are essential for the growth of solid tumors as well asfor other diseases.

CDKs constitute a class of enzymes that play critical roles inregulating the transitions between different phases of the cell cycle,such as the progression from a quiescent stage in G₁ (the gap betweenmitosis and the onset of DNA replication for a new round of celldivision) to S (the period of active DNA synthesis), or the progressionfrom G₂ to M phase, in which active mitosis and cell-division occur.See, e.g., the articles compiled in Science, vol. 274 (1996), pp.1643-1677; and Ann. Rev. Cell Dev. Biol., vol. 13 (1997), pp. 261-291.CDK complexes are formed through association of a regulatory cyclinsubunit (e.g., cyclin A, B1, B2, D1, D2, D3, and E) and a catalytickinase subunit (e.g., cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6). As thename implies, the GDKs display an absolute dependence on the cyclinsubunit in order to phosphorylate their target substrates, and differentkinase/cyclin pairs function to regulate progression through specificportions of the cell cycle.

The D cyclins are sensitive to extracellular growth signals and becomeactivated in response to mitogens during the G₁ phase of the cell cycle.CDK4/cyclin D plays an important role in cell cycle progression byphosphorylating, and thereby inactivating, the retinoblastoma protein(Rb). Hypophosphorylated Rb binds to a family of transcriptionalregulators, but upon hyperphosphorylation of Rb by CDK4/cyclin D, thesetranscription factors are released to activate genes whose products areresponsible for S phase progression. Rb phosphorylation and inactivationby CDK4/cyclin D permit passage of the cell beyond the restriction pointof the G₁ phase, whereupon sensitivity to extracellular growth orinhibitory signals is lost and the cell is committed to cell division.During late G₁, Rb is also phosphorylated and inactivated by CDK2/cyclinE, and recent evidence indicates that CDK2/cyclin E can also regulateprogression into S phase through a parallel pathway that is independentof Rb phosphorylation (see Lukas et al., “Cyclin E-induced S PhaseWithout Activation of the pRb/E2F Pathway,” Genes and Dev., vol. 11(1997), pp. 1479-1492).

The progression from G₁ to S phase, accomplished by the action ofCDK4/cyclin D and CDK2/cyclin E, is subject to a variety of growthregulatory mechanisms, both negative and positive. Growth stimuli, suchas mitogens, cause increased synthesis of cyclin D1 and thus increasedfunctional CDK4. By contrast, cell growth can be “reined in,” inresponse to DNA damage or negative growth stimuli, by the induction ofendogenous inhibitory proteins. These naturally occurring proteininhibitors include p₂₁ ^(WAF1/CIP1), p27^(KIP1), and the p16^(INK4)family, the latter of which inhibit CDK4 exclusively (see Harper,“Cyclin Dependent Kinase Inhibitors,” Cancer Surv., vol. 29 (1997), pp.91-107). Aberrations in this control system, particularly those thataffect the function of CDK4 and CDK2, are implicated in the advancementof cells to the highly proliferative state characteristic ofmalignancies, such as familial melanomas, esophageal carcinomas, andpancreatic cancers (see, e.g., Hall and Peters, “Genetic Alterations ofCyclins, Cyclin-Dependent Kinases, and CDK Inhibitors in Human Cancer,”Adv. Cancer Res., vol. 68 (1996), pp.67-108; and Kamb et al., “A CellCycle Regulator Potentially Involved in Genesis of Many Tumor Types,”Science, vol. 264 (1994), pp. 436-440). Over-expression of cyclin D1 islinked to esophageal, breast, and squamous cell carcinomas (see, e.g.,DelSal et al., “Cell Cycle and Cancer: Critical Events at the G₁Restriction Point,” Critical Rev. Oncogenesis, vol. 71 (1996), pp.127-142). Genes encoding the CDK4-specific inhibitors of the p16 familyfrequently have deletions and mutations in familial melanoma, gliomas,leukemias, sarcomas, and pancreatic, non-small cell lung, and head andneck carcinomas (see Nobori et al., “Deletions of the Cyclin-DependentKinase-4 Inhibitor Gene in Multiple Human Cancers,” Nature, vol. 368(1994), pp. 753-756). Amplification and/or overexpression of cyclin Ehas also been observed in a wide variety of solid tumors, and elevatedcyclin E levels have been correlated with poor prognosis. In addition,the cellular levels of the CDK inhibitor p27, which acts as both asubstrate and inhibitor of CDK2/cyclin E, are abnormally low in breast,colon, and prostate cancers, and the expression levels of p27 areinversely correlated with the stage of disease (see Loda et al.,“Increased Proteasome-dependent Degradation of the Cyclin-DependentKinase Inhibitor p27 in Aggressive Colorectal Carcinomas,” NatureMedicine, vol. 3 (1997), pp. 231-234). Recently there is evidence thatCDK4/cyclin D might sequester p27, as reviewed in Sherr, et al., GenesDev., Vol. 13 (1999), pp. 1501-1512. The p21 proteins also appear totransmit the p53 tumor-suppression signal to the CDKs; thus, themutation of p53 in approximately 50% of all human cancers may indirectlyresult in deregulation of CDK activity.

The emerging data provide strong validation for the use of compoundsinhibiting CDKs, and CDK4 and CDK2 in particular, as anti-proliferativetherapeutic agents. Certain biomolecules have been proposed for thispurpose. For example, U.S. Pat. No. 5,621,082 to Xiong et al. disclosesnucleic acid encoding of inhibitors of CDK6, and WO 99/06540 for CDK's.Peptides and peptidomimetic inhibitors are described in European PatentPublication No. 0 666 270 A2, Bandara, et al., Nature Biotechnology,Vol. 15 (1997), pp. 896-901 and Chen, et al., Proceedings of theNational Academy of Science, USA, Vol. 96 (1999), pp. 4325-4329. Peptideaptamers were identified from screening in Cohen, et al., Proc. Natl.Acad. Sci. U. S. A., Vol. 95 (1998), pp. 14272-14277. Several smallmolecules have been identified as CDK inhibitors (for recent reviews,see Webster, “The Therapeutic Potential of Targeting the Cell Cycle,”Exp. Opin. Invest. Drugs, vol. 7 (1998), pp. 865-887, and Stover, etal., “Recent advances in protein kinase inhibition: current molecularscaffolds used for inhibitor synthesis,” Current Opinion in DrugDiscovery and Development, Vol. 2 (1999), pp. 274-285). The flavoneflavopiridol displays modest selectivity for inhibition of CDKs overother kinases, but inhibits CDK4, CDK2, and CDK1 equipotently, withIC₅₀s in the 0.1-0.3 μM range. Flavopiridol is currently in Phase IIclinical trials as an oncology chemotherapeutic (Sedlacek et al.,“Flavopiridol (L86-8275; NSC 649890), A New Kinase Inhibitor for TumorTherapy,” lnt J. Oncol., vol. 9 (1996), pp. 1143-1168). Analogs offlavopiridol are the subject of other publications, for example, U.S.Pat. No. 5,733,920 to Mansuri et al. (International Publication No. WO97/16447) and International Publication Nos. WO 97/42949, and WO98/17662. Results with purine-based derivatives are described in Schowet al., Bioorg. Med. Chem. Lett., vol. 7 (1997), pp. 2697-2702; Grant etal., Proc. Amer. Assoc. Cancer Res,. vol. 39 (1998), Abst. 1207;Legravend et al., Bioorg. Med. Chem. Leff., vol. 8 (1998), pp. 793-798;Gray et al., Science, vol. 281 (1998), pp. 533-538; Chang, et al.,Chemistry & Biology, Vol. 6 (1999), pp. 361-375, WO 99/ 02162, WO99/43675, and WO 99/43676. In addition, the following publicationsdisclose certain pyrimidines that inhibit cyclin-dependent kinases andgrowth-factor mediated kinases: International Publication No. WO98/33798; Ruetz et al., Proc. Amer. Assoc. Cancer Res,. vol. 39 (1998),Abst. 3796; and Meyer et al., Proc. Amer. Assoc. Cancer Res., vol. 39(1998), Abst. 3794.

Benzensulfonamides that block cells in G1 are in development by Eisai,see Owa, et al., J. Med. Chem., Vol. 42 (1999), pp. 3789-3799. Anoxindole CDK inhibitor is in development by Glaxo-Wellcome, see Luzzio,et al., Proc. Amer. Assoc. Cancer Res., Vol. (1999), Abst. 4102 andWO99/15500. Paullones were found in collaboration with the NCI, Schultz,et al., J. Med. Chem., Vol. (1999), pp. 2909-2919. Indenopyrazoles aredescribed in WO99/17769 and by Seitz, et al, 218^(th) ACS Natl. Mtg.(Aug. 22-26, 1999, New Orleans), Abst MEDI 316. Aminothiazoles are usedin WO99/24416 and WO99/21845.

CHK1 is another protein kinase. CHK 1 plays an important role as acheckpoint in cell cycle progression. Checkpoints are control systemsthat coordinate cell cycle progression by influencing the formation,activation and subsequent inactivation of the cyclin-dependent kinases.Checkpoints prevent cell cycle progression at inappropriate times,maintain the metabolic balance of cells while the cell is arrested, andin some instances can induce apoptosis (programmed cell death) when therequirements of the checkpoint have not been met. See, e.g., O'Connor,Cancer Surveys, 29, 151-182 (1997); Nurse, Cell, 91, 865-867 (1997);Hartwell et al., Science, 266, 1821-1828 (1994); Hartwell et al.,Science, 246, 629-634 (1989).

One series of checkpoints monitors the integrity of the genome and, uponsensing DNA damage, these “DNA damage checkpoints” block cell cycleprogression in G₁ & G₂ phases, and slow progression through S phase.O'Connor, Cancer Surveys, 29, 151-182 (1997); Hartwell et al., Science,266, 1821-1828 (1994). This action enables DNA repair processes tocomplete their tasks before replication of the genome and subsequentseparation of this genetic material into new daughter cells takes place.Importantly, the most commonly mutated gene in human cancer, the p53tumor suppressor gene, produces a DNA damage checkpoint protein thatblocks cell cycle progression in G₁ phase and/or induces apoptosis(programmed cell death) following DNA damage. Hartwell et al., Science,266, 1821-1828 (1994). The p53 tumor suppressor has also been shown tostrengthen the action of a DNA damage checkpoint in G₂ phase of the cellcycle. See, e.g., Bunz et al., Science, 28, 1497-1501 (1998); Winters etal., Oncogene, 17, 673-684 (1998); Thompson, Oncogene, 15, 3025-3035(1997).

Given the pivotal nature of the p53 tumor suppressor pathway in humancancer, therapeutic interventions that exploit vulnerabilities inp53-defective cancer have been actively sought. One emergingvulnerability lies in the operation of the G₂ checkpoint in p53defective cancer cells. Cancer cells, because they lack G₁ checkpointcontrol, are particularly vulnerable to abrogation of the last remainingbarrier protecting them from the cancer killing effects of DNA-damagingagents: the G₂ checkpoint. The G₂ checkpoint is regulated by a controlsystem that has been conserved from yeast to humans. Important in thisconserved system is a kinase, CHK1, which transduces signals from theDNA-damage sensory complex to inhibit activation of the cyclin B/Cdc2kinase, which promotes mitotic entry. See, e.g., Peng et al., Science,277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997).Inactivation of CHK1 has been shown to both abrogate G₂ arrest inducedby DNA damage inflicted by either anticancer agents or endogenous DNAdamage, as well as result in preferential killing of the resultingcheckpoint defective cells. See, e.g., Nurse, Cell, 91, 865-867 (1997);Weinert, Science, 277, 1450-1451 (1997); Walworth et al., Nature, 363,368-371 (1993); and AI-Khodairy et al., Molec. Biol. Cell, 5, 147-160(1994).

Selective manipulation of checkpoint control in cancer cells couldafford broad utilization in cancer chemotherapeutic and radiotherapyregimens and may, in addition, offer a common hallmark of human cancer“genomic instability” to be exploited as the selective basis for thedestruction of cancer cells. A number of factors place CHK1 as a pivotaltarget in DNA-damage checkpoint control. The elucidation of inhibitorsof this and functionally related kinases such as CDS1/CHK2, a kinaserecently discovered to cooperate with CHK1 in regulating S phaseprogression (see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka,Science, 282, 1893-1897 (1998)), could provide valuable new therapeuticentities for the treatment of cancer.

Another group of kinases are the tyrosine kinases. Tyrosine kinases canbe of the receptor type (having extracellular, transmembrane andintracellular domains) or the non-receptor type (being whollyintracellular). At least one of the non-receptor protein tyrosinekinases, namely, LCK, is believed to mediate the transduction in T-cellsof a signal from the interaction of a cell-surface protein (Cd4) with across-linked anti-Cd4 antibody. A more detailed discussion ofnon-receptor tyrosine kinases is provided in Bolen, Oncogene, 8,2025-2031 (1993), which is incorporated herein by reference.

In addition to its role in cell-cycle control, protein kinases also playa crucial role in angiogenesis, which is the mechanism by which newcapillaries are formed from existing vessels. When required, thevascular system has the potential to generate new capillary networks inorder to maintain the proper functioning of tissues and organs. In theadult, however, angiogenesis is fairly limited, occurring only in theprocess of wound healing and neovascularization of the endometriumduring menstruation. See Merenmies, J., Parada, L. F., Henkemeyer, M.,Cell Growth & Differentiation, 8, 3-10 (1997). On the other hand,unwanted angiogenesis is a hallmark of several diseases, such asretinopathies, psoriasis, rheumatoid arthritis, age-related maculardegeneneration, and cancer (solid tumors). Folkman, Nature Med., 1,27-31 (1995). Protein kinases which have been shown to be involved inthe angiogenic process include three members of the growth factorreceptor tyrosine kinase family: VEGF-R2 (vascular endothelial growthfactor receptor 2, also know as KDR (kinase insert domain receptor) andas FLK-1); FGF-R (fibroblast growth factor receptor); and TEK (alsoknown as Tie-2).

VEGF-R2, which is expressed only on endothelial cells, binds the potentangiogenic growth factor VEGF and mediates the subsequent signaltransduction through activation of its intracellular kinase activity.Thus, it is expected that direct inhibition of the kinase activity ofVEGF-R2 will result in the reduction of angiogenesis even in thepresence of exogenous VEGF (see Strawn et al., Cancer Research, 56,3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which failto mediate signal transduction. Millauer et al., Cancer Research, 56,1615-1620 (1996). Furthermore, VEGF-R2 appears to have no function inthe adult beyond that of mediating the angiogenic activity of VEGF.Therefore, a selective inhibitor of the kinase activity of VEGF-R2 wouldbe expected to exhibit little toxicity.

Similarly, FGF-R binds the angiogenic growth factors aFGF and bFGF andmediates subsequent intracellular signal transduction. Recently, it hasbeen suggested that growth factors such as bFGF may play a critical rolein inducing angiogenesis in solid tumors that have reached a certainsize. Yoshiji et al., Cancer Research, 57, 3924-3928 (1997). UnlikeVEGF-R2, however, FGF-R is expressed in a number of different cell typesthroughout the body and may or may not play important roles in othernormal physiological processes in the adult. Nonetheless, systemicadministration of a small molecule inhibitor of the kinase activity ofFGF-R has been reported to block bFGF-induced angiogenesis in micewithout apparent toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904(1998).

TEK (also known as Tie-2) is another receptor tyrosine kinase expressedonly on endothelial cells which has been shown to play a role inangiogenesis. The binding of the factor angiopoietin-1 results inautophosphorylation of the kinase domain of TEK and results in a signaltransduction process which appears to mediate the interaction ofendothelial cells with peri-endothelial support cells, therebyfacilitating the maturation of newly formed blood vessels. The factorangiopoietin-2, on the other hand, appears to antagonize the action ofangiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al.,Science, 277, 55-60 (1997).

As a result of the above-described developments, it has been proposed totreat angiogenesis by the use of compounds inhibiting the kinaseactivity of VEGF-R2, FGF-R, and/or TEK. For example, WIPO InternationalPublication No. WO 97/34876 discloses certain cinnoline derivatives thatare inhibitors of VEGF-R2, which may be used for the treatment ofdisease states associated with abnormal angiogenesis and/or increasedvascular permeability such as cancer, diabetes, psoriosis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restinosis, autoimmune diseases, acuteinflammation and ocular diseases with retinal vessel proliferation. Inaddition to the protein kinases identified above, many other proteinkinases have been considered to be therapeutic targets, and numerouspublications disclose inhibitors of kinase activity, as reviewed in thefollowing: McMahon et al., Current Opinion in Drug Discovery &Development, 1, 131-146 (1998); Strawn et al., Exp. Opin. Invest. Drugs,7, 553-573 (1998).

There is still a need, however, for other small-molecule compounds thatmay be readily synthesized and are potent inhibitors of cellproliferation, for example, inhibitors of one or more protein kinases,such as CHK1, VEGF, CDKs or CDK/cyclin complexes. Because CDK4 may serveas a general activator of cell division in most cells, and becausecomplexes of CDK4/cyclin D and CDK2/cyclin E govern the early G₁ phaseof the cell cycle, there is a need for effective and specific inhibitorsof CDK4 and/or CDK2 for treating one or more types of tumors.

SUMMARY OF THE INVENTION

An object of the invention is to provide potent anti-proliferativeagents. Accordingly, one object of the invention is to attain compoundsand drug compositions that inhibit the activity of one or more kinases,such as CDKs, VEGF, and CHK-1, or cyclin complexes thereof. A furtherobject is to provide an effective method of treating cancer indicationsthrough kinases inhibition, such as through inhibition of VEGF, CHK-1,CDK4 or CDK4/D-type cyclin complexes and/or CDK2 or CDK2/E-type cyclincomplexes. Another object is to achieve pharmaceutical compositionscontaining compounds effective to block the transition of cancer cellsinto their proliferative phase. These and other objects and advantagesof the invention, which will become apparent in light of the detaileddescription below, are achieved through use of cell-cycle control agentsof the invention described below.

According to these objectives, there is provided in accordance with thepresent invention a compound represented by the Formula I

wherein:

R₁ is a substituted or unsubstituted alkyl, aryl, heteroaryl,carbocycle, or heterocycle group, or

 wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, heteroaryl, carbocycle, or heterocycle group; and

R₂ is a substituted or unsubstituted alkyl, aryl, heteroaryl,carbocycle, or heterocycle group, or

 wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedaryl, heteroaryl, carbocycle, or heterocycle group; or

a pharmaceutically acceptable salt of a compound of the Formula I; or aprodrug or pharmaceutically active metabolite of a compound of theFormula I, or a pharmaceutically acceptable salt of the prodrug ormetabolite. According to these objectives, there is also provided acompound represented by Formula II:

wherein

R′₁ is a substituted or unsubstituted alkyl, aryl, heteroaryl,carbocycle, heterocycle,

or

group,

wherein each R₄ is individually H or lower alkyl and X is a substitutedor unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocyclegroup; and

R′₂ is a substituted or unsubstituted amino, nitro, alkenyl, alkyl,aryl, heteroaryl, carbocycle, heterocycle,

or

group,

 wherein R₄ is independently H or lower alkyl, and X is a substituted orunsubstituted aryl, heteroaryl, carbocycle, or

heterocycle group; or

a pharmaceutically acceptable salt of a compound of the Formula II; or aprodrug or pharmaceutically active metabolite of a compound of theFormula II, or a pharmaceutically acceptable salt of the prodrug ormetabolite thereof. There is also provided in accordance with theinvention, a pharmaceutical composition comprising:

(a) a cell-cycle control agent selected from:

(i) a compound of the Formula I or II,

(ii) a pharmaceutically acceptable salt of a compound of the Formula Ior II; or

(iii) a prodrug or pharmaceutically active metabolite of a compound ofthe Formula I or II, or a pharmaceutically acceptable salt of theprodrug or metabolite; and

(b) a pharmaceutically acceptable carrier.

The invention also provides methods for making compounds of Formula Iand II.

There is further provided in accordance with the invention, a method ofusing a compound as a cell-cycle control agent for treating a disease ordisorder mediated by inhibition of kinase comprising administering to apatient in need thereof, a compound of Formula I or II, or apharmaceutically acceptable salt of a compound of the Formula I or II;or a prodrug or pharmaceutically active metabolite of a compound of theFormula I or II, or a pharmaceutically acceptable salt of the metaboliteor prodrug.

The invention further provides a method of treating mycotic infection,malignancies or cancer as well as other disease states associated withunwanted angiogenesis and/or cellular proliferation, comprisingadministering effective amounts of a compound of Formula I or II or apharmaceutically acceptable salt of a compound of the Formula I or II;or a prodrug or pharmaceutically active metabolite of a compound of theFormula I or II, or a pharmaceutically acceptable salt of the metaboliteor prodrug, to a patient in need of such treatment.

The invention also provides a method of modulating and/or inhibitingkinase activity by administering a compound of the Formula I or II or apharmaceutically acceptable salt of a compound of the Formula I or II;or a prodrug or pharmaceutically active metabolite of a compound of theFormula I or II, or a pharmaceutically acceptable salt of the metaboliteor prodrug, to a patient in need thereof.

There is also provided in accordance with the invention, apharmaceutical composition containing a compound of the Formula I or IIor a pharmaceutically acceptable salt of a compound of the Formula I orII; or a prodrug, or pharmaceutically active metabolite of a compound ofthe Formula I or II, or a pharmaceutically acceptable salt of themetabolite or prodrug, and the therapeutic use of the composition intreating diseases mediated by kinase activity, such as cancer, as wellas other disease states associated with unwanted angiogenesis and/orcellular proliferation, such as diabetic retinopathy, neovascularglaucoma, rheumatoid arthritis, and psoriasis.

For the pharmaceutical composition and method aspects of the invention,R₁ can also be hydrogen, in Formula I and II.

The inventive agents and compositions containing such agents may beuseful in treating various disorders or disease states associated withuncontrolled or unwanted cellular proliferation, such as cancer,autoimmune disorders, viral diseases, fungal diseases, neurodegenerativedisorders, and cardiovascular diseases. Thus, the invention is alsodirected to methods of treating such diseases by administering aneffective amount of the inventive agent.

Other aspects, advantages, and features of the invention will becomeapparent from the detailed description below.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS OF THE INVENTION

The compounds and compositions of the present invention, are useful asanti-proliferative agents and as inhibitors of mammalian kinasecomplexes, insect kinase or fungal kinase complexes. For example, VEGF,CHK-1, and/or CDK complexes can be inhibited. Such compounds andcompositions are also useful for controlling proliferation,differentiation, and/or apoptosis.

Examples of R₁, R₂, R′₁, and R′₂ preferred in compounds of Formula I orII groups are set forth below:

Preferably R₁ and R′₁ are:

wherein Y is CH or N or CR₃, X is as defined above and R₃ is H, or oneor more substituents located on the ring, such as a substituted orunsubstituted alkyl, alkenyl, aryl, heteroaryl, carbocycle, heterocycle,hydroxy, halogen, alkoxy, aryloxy, heteroaryloxy, thioalkyl, thioaryl,thioacyl, thioheteroaryl or amino; or

 wherein the two Y's can be the same or different.

In those embodiments, wherein R₁ or R′₁ is

there can be one or more R₃ substituents on the phenyl ring.

More preferably, R₁ and R′₁ are substituted or unsubstituted

wherein the R₃ groups are as defined above. Also, two R₃'s together withan adjacent nitrogen can form a heteroaryl or heterocycle ring.

Preferably, R₂ and R′₂ are unsubstituted or substituted phenyl or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedgroup selected from alkyl, aryl, heteroaryl, carbocycle, or heterocycle.

Other preferred R₂ and R′₂ groups are substituted or unsubstitutedheteroaryls such as

Other preferred R₂ and R′₂ groups are

where R₃ is as defined above.

Especially preferred substituents for the phenyl of R₂ include fluorine,chlorine, hydroxyl, or an alkoxy group, such as methoxy. Examples ofpreferred R groups, X, and Y groups are found in the exemplary compoundsthat follow.

Y is preferably nitrogen.

X is preferably aryl, heteroaryl, carbocycle, or heterocycle, mostpreferably phenyl.

R₂ and R′₂ can also be an amino (−NR′R″), wherein R′ and R″ areindependently as defined for R₃ above, and together with an adjacentnitrogen can form a ring.

R₄ is preferably hydrogen, or can be a lower alkyl having 1-6 carbonatoms, which may be substituted or unsubstituted. The two R₄'s can bethe same or different.

Other preferred R₁, R₂, R′₁, and R′₂ groups are found in the exemplarycompounds that follow.

Any desired alkyl group can be used, e.g., as R₁ or R₂ or R′₁ or R′₂ orR₃ or X. The alkyl group can be a straight- or branched-chain alkylgroup having one to twelve carbon atoms. Exemplary alkyl groups includemethyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and thelike. The alkyl can be substituted or unsubstituted. Preferredsubstituted alkyls include fluoromethyl, difluoromethyl,trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, and the like.

Any desired aryl, heteroaryl, carbocycle, or heterocycle group can beused as, e.g., R₁ or R₂ or R′₁ or R′₂ or R₃ or X. The groups can befused or non-fused, monocyclic or polycyclic.

Preferred aryl and heteroaryl groups include monocyclic and polycyclicunsaturated or aromatic ring structures, with “aryl” referring to thosethat are carbocycles and “heteroaryl” referring to those that areheterocycles. Examples of ring structures include phenyl, naphthyl,1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridyl,pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl,1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1-H-tetrazol-5-yl, indolyl, quinolinyl, benzothiophenyl(thianaphthenyl), furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, triazolyl, tetrazolyl, isoquinolinyl, acridinyl, pyrimidinyl,benzimidazolyl, benzofuranyl, and the like.

Preferred carbocyclic groups include those having from three to twelvecarbon atoms, including bicyclic and tricyclic cycloalkyl structures.Preferred carbocyclic groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and the like.

Preferred heterocyclic groups include saturated rings containing carbonatoms, for example containing 4 or 5 ring carbon atoms, and at least oneheteroatom selected from nitrogen, oxygen and sulfur, and having nounsaturation. Preferred heterocyclic groups include pyrrolidinyl,piperidinyl, thiazinyl, and morpholinyl.

R₁, R₂, R₃, Y, X, and other R groups can be unsubstituted or substitutedwith any desired substituent or substituents that do not adverselyaffect the desired activity of the compound. Examples of preferredsubstituents are those found in the exemplary compounds that follows, aswell as halogen (chloro, iodo, bromo, or fluoro); C₁₋₆-alkyl;C₁₋₆-alkenyl; C₁₋₆-alkynyl; hydroxyl; C₁₋₆ alkoxyl; amino; nitro; thiol;thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl;thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen(═O); haloalkyl (e.g., trifluoromethyl); carbocyclic cycloalkyl, whichmay be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, whichmay be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic orheterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g.,phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl,pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino(primary, secondary, or tertiary); nitro; thiol; thioether, 0-loweralkyl; 0-aryl, aryl; aryl-lower alkyl; CO₂CH₃; CONH₂; OCH₂CONH₂; NH₂;SO₂NH₂; OCHF₂; CF₃; OCF₃; an Such moieties may also be optionallysubstituted by a fused-ring structure or bridge, for example OCH₂—O.

These substituents may optionally be further substituted with asubstituent selected from such groups.

Preferred compounds are shown in the examples that follow as well as:

The present invention also relates to intermediates useful in thepreparation of compounds of Formula I or II. A particularly preferredintermediate has the structure

Another preferred intermediate has the structure

Another preferred intermediate has the structure

In place of SEM, in the above three intermediates, other knownprotecting groups, such as benzyloxycarbonyl (CBZ), tert-butoxycarbonyl(BOC), tetra hydropyranyl (THP), and fluorene-9-methyloxycarbonyl(FMOC), can be used.

Other preferred intermediates include

The abbreviations “SEM” and “PMB” refer to (trimethyl silyl) ethoxymethyl and p-methoxybenzyl, respectively.

A preferred intermediate has the structure

wherein PG is a protecting group, T is a reactive group such as asubstituted or unsubstituted boron, halogen, NO₂, or NH₂ group, and T′is a reactive group such as CHO, CO₂H, CO₂R₃, CONR₃R₃, where R₃ groupsare as defined above.

Pharmaceutical compositions according to the invention may,alternatively or in addition to a compound of the Formula I or II,comprise as an active ingredient a pharmaceutically acceptable salt of acompound of the Formula I or II, or a prodrug or pharmaceutically activemetabolite of such a compound or salt or a salt of the prodrug ormetabolite. Such compounds, salts, prodrugs, and metabolites aresometimes referred to herein collectively as “cell-cycle controlagents.”

The term “prodrug” refers to a metabolic precursor of a compound of theFormula I or II (or a salt thereof) that is pharmaceutically acceptable.A prodrug may be inactive when administered to a subject but isconverted in vivo to an active compound of the Formula I or II. The term“active metabolite” refers to a metabolic product of a compound of theFormula I or II that is pharmaceutically acceptable and effective.Prodrugs and active metabolites of compounds of the Formula I or II maybe determined using techniques known in the art.

Prodrugs and active metabolites of a compound may be identified usingroutine techniques known in the art. See, e.g., Bertolini et al., J.Med. Chem., 40, 2011-2016 (1997); Shan, et al., J. Pharm. Sci., 86 (7),765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advancesin Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs(Elsevier Press 1985); and Larsen, Design and Application of Prodrugs,Drug Design and Development (Krogsgaard-Larsen et al., eds., HarwoodAcademic Publishers, 1991).

Within the invention it is understood that a compound of Formula I or IImay exhibit the phenomenon of tautomerism and that the formula drawingswithin this specification represent only one of the possible tautomericforms. It is to be understood that the invention encompasses anytautomeric form which modulates and/or inhibits kinase activity and isnot to be limited merely to any one tautomeric form utilized within theformula drawings.

Some of the inventive compounds may exist as single stereoisomers (i.e.,essentially free of other stereoisomers), racemates, and/or mixtures ofenantiomers and/or diastereomers. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthe present invention. Preferably, the inventive compounds that areoptically active are used in optically pure form.

As generally understood by those skilled in the art, an optically purecompound having one chiral center (i.e., one asymmetric carbon atom) isone that consists essentially of one of the two possible enantiomers(i.e., is enantiomerically pure), and an optically pure compound havingmore than one chiral center is one that is both diastereomerically pureand enantiomerically pure. Preferably, the compounds of the presentinvention are used in a form that is at least 90% optically pure, thatis, a form that contains at least 90% of a single isomer (80%enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”)), morepreferably at least 95% (90% e.e. or d.e.), even more preferably atleast 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98%e.e. or d.e.).

Additionally, Formulas I and II are intended to cover solvated as wellas unsolvated forms of the identified structures. For example, FormulasI and II include compounds of the indicated structure in both hydratedand non-hydrated forms. Other examples of solvates include thestructures in combination with isopropanol, ethanol, methanol, DMSO,ethyl acetate, acetic acid, or ethanolamine.

“A pharmaceutically acceptable salt” is intended to mean a salt thatretains the biological effectiveness of the free acids and bases of thespecified compound and that is not biologically or otherwiseundesirable. A compound of the invention may possess a sufficientlyacidic, a sufficiently basic, or both functional groups, and accordinglyreact with any of a number of inorganic or organic bases, and inorganicand organic acids, to form a pharmaceutically acceptable salt. Exemplarypharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with a mineral ororganic acid or an inorganic base, such as salts including sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyrovic acid, oxalic acid, glycolic acid, salicylic acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid,such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid or cinnamic acid, a sulfonic acid, such asp-toluenesulfonic acid or ethanesulfonic acid, or the like. If theinventive compound is an acid, the desired pharmaceutically acceptablesalt may be prepared by any suitable method, for example, treatment ofthe free acid with an inorganic or organic base, such as an amine(primary, secondary or tertiary), an alkali metal hydroxide or alkalineearth metal hydroxide, or the like. Illustrative examples of suitablesalts include organic salts derived from amino acids, such as glycineand arginine, ammonia, primary, secondary, and tertiary amines, andcyclic amines, such as piperidine, morpholine and piperazine, andinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum and lithium.

In the case of agents that are solids, it is understood by those skilledin the art that the inventive compounds and salts may exist in differentcrystal or polymorphic forms, all of which are intended to be within thescope of the present invention and specified formulas.

Cell-cycle control agents in accordance with the invention are useful aspharmaceuticals for treating proliferative disorders in mammals,especially humans, marked by unwanted proliferation of endogenoustissue. Compounds of the Formula I or II may be used for treatingsubjects having a disorder associated with excessive cell proliferation,e.g., cancers, psoriasis, immunological disorders involving undesiredproliferation of leukocytes, and restenosis and other smooth-muscledisorders. Furthermore, such compounds may be used to preventde-differentiation of post-mitotic tissue and/or cells.

Diseases or disorders associated with uncontrolled or abnormal cellularproliferation include, but are not limited to, the following:

a variety of cancers, including, but not limited to, carcinoma,hematopoietic tumors of lymphoid lineage, hematopoietic tumors ofmyeloid lineage, tumors of mesenchymal origin, tumors of the central andperipheral nervous system and other tumors including melanoma, seminomaand Kaposi's sarcoma and the like.

a disease process which features abnormal cellular proliferation, e.g.,benign prostatic hyperplasia, familial adenomatosis polyposis,neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis,psoriasis, glomerulonephritis, restenosis following angioplasty orvascular surgery, hypertrophic scar formation, inflammatory boweldisease, transplantation rejection, endotoxic shock, and fungalinfections.

defective apoptosis-associated conditions, such as cancers (includingbut not limited to those types mentioned hereinabove), viral infections(including but not limited to herpesvirus, poxvirus, Epstein-Barr virus,Sindbis virus and adenovirus), prevention of AIDS development inHIV-infected individuals, autoimmune diseases (including but not limitedto systemic lupus erythematosus, rheumatoid arthritis, psoriasis,autoimmune mediated glomerulonephritis, inflammatory bowel disease andautoimmune diabetes mellitus), neurodegenerative disorders (includingbut not limited to Alzheimer's disease, amyotrophic lateral sclerosis,retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinalmuscular atrophy and cerebellar degeneration), myelodysplasticsyndromes, aplastic anemia, ischemic injury associated with myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, hematological diseases(including but not limited to chronic anemia and aplastic anemia),degenerative diseases of the musculoskeletal system (including but notlimited to osteroporosis and arthritis), aspirin-sensitiverhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases andcancer pain.

The active agents of the invention may also be useful in the inhibitionof the development of invasive cancer, tumor angiogenesis andmetastasis.

Moreover, the active agents of the invention, for example, as inhibitorsof the CDKs, can modulate the level of cellular RNA and DNA synthesisand therefore are expected to be useful in the treatment of viralinfections such as HIV, human papilloma virus, herpes virus,Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like.

Compounds and compositions of the invention inhibit the kinase activityof, for example, CDK/cyclin complexes, such as those active in the G₀ orG₁ stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6 complexes.

The specific dosage amount of a cell-cycle control agent beingadministered to obtain therapeutic or inhibitory effects may bedetermined in a manner known in the art according to the particularcircumstances surrounding the case, including, e.g., the specific agentbeing administered, the route of administration, the condition beingtreated, and the subject or host being treated. An exemplary total dailydose of a cell-cycle control agent, which may be administered in singleor multiple doses, contains a dosage level of from about 0.01 mg/kg bodyweight to about 50 mg/kg body weight.

The cell-cycle control agents of the invention may be administered byany of a variety of suitable routes, such as orally, rectally,transdermally, subcutaneously, intravenously, intramuscularly, orintranasally. The cell-cycle control agents are preferably formulatedinto compositions suitable for the desired routes before beingadministered.

A pharmaceutical composition or preparation according to the inventioncomprises an effective amount of a cell-cycle control agent, optionallyone or more other active agents, and a pharmaceutically acceptablecarrier, such as a diluent or excipient for the agent; when the carrierserves as a diluent, it may be a solid, semi-solid, or liquid materialacting as a vehicle, excipient, or medium for the active ingredient(s).Compositions according to the invention may be made by admixing theactive ingredient(s) with a carrier, or diluting it with a carrier, orenclosing or encapsulating it within a carrier, which may be in the formof a capsule, sachet, paper container, or the like. Exemplaryingredients, in addition to one or more cell-cycle control agents andany other active ingredients, include Avicel (microcrystallinecellulose), starch, lactose, calcium sulfate dihydrate, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid, peanut oil, olive oil, glyceryl monostearate, Tween 80(polysorbate 80), 1,3-butanediol, cocoa butter, beeswax, polyethyleneglycol, propylene glycol, sorbitan monostearate, polysorbate 60,2-octyldodecanol, benzyl alcohol, glycine, sorbic acid, potassiumsorbate, disodium hydrogen phosphate, sodium chloride, and water.

The compositions may be prepared in any of a variety of forms suitablefor the desired mode of administration. For example, pharmaceuticalcompositions may be prepared in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as solids or in liquid media), ointments (e.g.,containing up to 10% by weight of a cell-cycle control agent), soft-geland hard-gel capsules, suppositories, sterile injectable solutions,sterile packaged powders, and the like.

Similarly, the carrier or diluent may include time-delay or time-releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate and the like.

A variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier may vary, but generally will befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation can be in the form of syrup, emulsion, soft gelatin capsule,sterile injectable solution or suspension in an ampoule or vial ornon-aqueous liquid suspension.

To obtain a stable water-soluble dose form, a pharmaceuticallyacceptable salt of an inventive agent is dissolved in an aqueoussolution of an organic or inorganic acid, such as 0.3M solution ofsuccinic acid or citric acid. If a soluble salt form is not available,the agent may be dissolved in a suitable cosolvent or combinations ofcosolvents. Examples of suitable cosolvents include, but are not limitedto, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80,gylcerin and the like in concentrations ranging from 0-60% of the totalvolume. A compound of Formula I or II may be dissolved in DMSO anddiluted with water. The composition may also be in the form of asolution of a salt form of the active ingredient in an appropriateaqueous vehicle such as water or isotonic saline or dextrose solution.

The compositions of the invention may be manufactured in mannersgenerally known for preparing pharmaceutical compositions, e.g., usingconventional techniques such as mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orlyophilizing. Pharmaceutical compositions may be formulated in aconventional manner using one or more physiologically acceptablecarriers, which may be selected from excipients and auxiliaries thatfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically.

Proper formulation is dependent upon the route of administration chosen.For injection, the agents of the invention may be formulated intoaqueous solutions, preferably in physiologically compatible buffers suchas Hanks's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carriersknown in the art. Such carriers enable the compounds of the invention tobe formulated as tablets, pills, dragees, capsules, liquids, gels,syrups, slurries, suspensions and the like, for oral ingestion by apatient to be treated. Pharmaceutical preparations for oral use can beobtained using a solid excipient in admixture with the active ingredient(agent), optionally grinding the resulting mixture, and processing themixture of granules after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include: fillerssuch as sugars, including lactose, sucrose, mannitol, or sorbitol; andcellulose preparations, for example, maize starch, wheat starch, ricestarch; potato starch, gelatin, gum, hydroxypropylmethyl-cellulose,sodium carboxymethylcellulose, methyl cellulose, or polyvinylpyrrolidone(PVP). If desired, disintegrating agents may be added, such ascrosslinked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol,and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillerssuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate, and, optionally, stabilizers. In softcapsules, the active agents may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration. For buccal administration, the compositions may take theform of tablets or lozenges formulated in conventional manner.

For administration intranasally or by inhalation, the compounds for useaccording to the present invention are conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator and the like may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit-dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active agents may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

For administration to the eye, the active agent is delivered in apharmaceutically acceptable ophthalmic vehicle such that the compound ismaintained in contact with the ocular surface for a sufficient timeperiod to allow the compound to penetrate the corneal and internalregions of the eye, including, for example, the anterior chamber,posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea,iris/ciliary, lens, choroid/retina and sclera. The pharmaceuticallyacceptable ophthalmic vehicle may be an ointment, vegetable oil, or anencapsulating material. A compound of the invention may also be injecteddirectly into the vitreous and aqueous humor.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use. The compounds may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

The compounds may also be formulated as a depot preparation. Suchlong-acting formulations may be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds may be formulated withsuitable polymeric or hydrophobic materials (for example, as an emulsionin an acceptable oil) or ion-exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

A pharmaceutical carrier for hydrophobic compounds is a cosolvent systemcomprising benzyl alcohol, a nonpolar surfactant, a water-miscibleorganic polymer, and an aqueous phase. The cosolvent system may be a VPDco-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v ofthe nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol300, made up to volume in absolute ethanol. The VPD co-solvent system(VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution.This co-solvent system dissolves hydrophobic compounds well, and itselfproduces low toxicity upon systemic administration. Naturally, theproportions of a co-solvent system may be varied considerably withoutdestroying its solubility and toxicity characteristics. Furthermore, theidentity of the co-solvent components may be varied: for example, otherlow-toxicity nonpolar surfactants may be used instead of polysorbate 80;the fraction size of polyethylene glycol may be varied; otherbiocompatible polymers may replace polyethylene glycol, e.g. polyvinylpyrrolidone; and other sugars or polysaccharides may be substituted fordextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are known examples ofdelivery vehicles or carriers for hydrophobic drugs. Certain organicsolvents such as dimethylsulfoxide also may be employed, althoughusually at the cost of greater toxicity. Additionally, the compounds maybe delivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials have been established and are knownby those skilled in the art. Sustained-release capsules may, dependingon their chemical nature, release the compounds for a few weeks up toover 100 days. Depending on the chemical nature and the biologicalstability of the therapeutic reagent, additional strategies for proteinstabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid- orgel-phase carriers or excipients. Examples of such carriers orexcipients include calcium carbonate, calcium phosphate, sugars,starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

Some of the compounds of the invention may be provided as salts withpharmaceutically compatible counter ions. Pharmaceutically compatiblesalts may be formed with many acids, including hydrochloric, sulfuric,acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree-base forms.

A pharmaceutical composition according to the invention comprises acell-cycle control agent and, optionally, one or more other activeingredients, such as a known antiproliferative agent that is compatiblewith the cell-cycle control agent and suitable for the indication beingtreated.

The compounds are useful as anti-angiogenesis agents and as agents formodulating and/or inhibiting the activity of protein kinases, thusproviding treatments for cancer or other diseases associated withcellular proliferation mediated by protein kinases.

Therapeutically effective amounts of the agents of the invention may beused to treat diseases mediated by modulation or regulation of proteinkinases. An “effective amount” is intended to mean that amount of anagent that, when administered to a mammal in need of such treatment, issufficient to effect treatment for a disease mediated by the activity ofone or more kinases. Thus, e.g., a therapeutically effective amount of acompound of the Formula I or II, salt, active metabolite or prodrugthereof is a quantity sufficient to modulate, regulate, or inhibit theactivity of one or more kinases such that a disease condition which ismediated by that activity is reduced or alleviated.

“Treating” is intended to mean at least the mitigation of a diseasecondition in a mammal, such as a human, that is affected, at least inpart, by the activity of one or more kinases, and includes: preventingthe disease condition from occurring in a mammal, particularly when themammal is found to be predisposed to having the disease condition buthas not yet been diagnosed as having it; modulating and/or inhibitingthe disease condition; and/or alleviating the disease condition.

The inventive agents may be prepared using the reaction routes andsynthesis schemes as described below, employing the techniques availablein the art using starting materials that are readily available.

Exemplary general Schemes 1-6, shown below, can be used to make thecompounds of the invention.

The halogenated intermediate A can be obtained by standard diatozationof 5-amino indazole and treatment of the resulting diazonium salt withan appropriate halide salt, such as CuCl or Kl. Further halogenation toafford the 3-haloindazole B is achieved by treatment with a suitablebase such as sodium hydroxide or potassium hydroxide and elementalhalogen such as iodine. Intermediate B is protected using any number ofsuitable protecting groups and treated with a (preferablystoichiometric) alkyl or aryl boronic acid or ester and a suitable Pdcatalyst, for example, Pd(PPh₃)₄, to affect selective reaction at theC-3 position. Further reaction with a second alkyl or aryl boronic acidor ester and a suitable Pd catalyst affords the desired3,5-disubstituted intermediate E which is then deprotected to afford thefinal compound F. Deprotection conditions are consistent with thespecific protecting group employed, for example, acidic conditions forremoval of a THP protecting group. R₁ and R₂ are as defined above, andcan be R′₁ and R′₂.

The above alternative synthetic variation to Route 1 involves treatmentof intermediate C wherein X is Cl with an alkyl ditin species, such ashexamethyl ditin, and an appropriate Pd catalyst, to afford intermediateG. Reaction of intermediate G with an alkyl or aryl halide and asuitable Pd catalyst provides the desired intermediate D which can befurther elaborated as described above.

Alternatively, as shown in Route 2 above, a 5-nitro indazole can behalogenated as described above for intermediate A, to afford nitrocompound H, by treatment with a suitable base such as sodium hydroxideor potassium hydroxide and elemental halogen such as iodine to yield anintermediate I after standard protection with an appropriate protectinggroup. Treatment of intermediate I with an alkyl ditin species, such ashexamethyl ditin, and a suitable Pd catalyst, can afford intermediate J.Further reaction of nitro compound J with an alkyl or aryl boronic acidor ester and a suitable Pd catalyst affords the 3-substituted indazoleK. Reduction of K with a suitable reducing agent, such as hydrogen withpalladium catalyst or SnCl₂, affords the amine. Diazotization of theresulting 5-amino indazole and treatment of the resulting diazonium saltwith a suitable halide salt, such as CuCl or Kl affords intermediatehalo compound L. Reaction of L with an alkyl or aryl boronic acid orester and a suitable Pd catalyst affords the intermediate M which isdeprotected as before to yield final compound F. R₁ and R₂ are asdefined above, and can be R′₁ and R′₂.

In Route 3 shown above, 3-carboxyindazole is activated to provide anactive acylating species, such as with carbonyldiimidazole, which isthen treated with a suitable alkoxy-alkyl amine, suchN,N-dimethylhydroxylamine, to afford the amide A′. Selectivehalogenation of intermediate A′ with elemental halogen such as bromineor iodine and preferably with a catalyst such asbis(trifluoroacetoxy)iodosobenzene or bis(acetoxy) iodosobenzene yieldsthe 5-halo indazole B′. Protection of intermediate B′ under standardconditions with a suitable protecting group such as PMB or THP affordsprotected amide C′. Reduction of C′ with an appropriate reductant suchas lithium aluminum hydride or an equivalent hydride reducing agentyields key intermediate aldehyde D′. R₃ is as defined above, and ispreferably substituted or unsubstituted alkyl, preferably lower alkyl.

In Route 4 shown above, intermediate D′ is reacted with a substituteddiamine B″ and a suitable oxidizing agent such as sulfur to afford thebenzimidazole C″. Conversion of compound C″ to the correspondingborinate ester D″ is accomplished by reacting with a suitable diboronspecies, such as dipinacolatodiboron, or other electrophilic source ofboron, with an appropriate palladium catalyst. Intermediate D″ isfurther reacted with a halogenated aryl or alkyl halide under palladiumcatalysis to give 5-substituted indazole intermediate E″, which afterappropriate deprotection affords the final compound H″.

Alternatively, starting compound D′ is reacted with a suitable diboronspecies, such as bis(pinacolato)diboron, or other suitable electrophilicsource of boron, and an appropriate palladium catalyst to give boronester F″. Elaboration of compound F″ into intermediate D″ isaccomplished as described before for intermediate D′.

Another alternative conversion can be accomplished by reactingintermediate aldehyde F′ with a substituted aryl or alkyl halide toprovide R₂ with a palladium catalyst to afford G″ which is furtherreacted with a substituted diamine B″ and a suitable oxidizing agentsuch as sulfur to afford the benzimidazole E″. Deprotection as beforeyields final compound H″. R₂ is as defined above and can be R′₂. R₃ isas defined above.

Yet another preparation of intermediate E″ can be accomplished byreacting compound such as C″ directly with a suitable alkyl borinic acidor ester under suitable palladium catalysis.

Additional electrophilic boron species that can be used have thestructure:

where R₃ is as defined above and two R₃ groups can form a ring.

Specific examples include:

In Route 5 above, alcohol intermediate X₁ can be activated for exampleby reaction with a sulfonyl halide such as methanesulfonyl chloride anda suitable base such as triethylamine and this electrophilic speciesreacted further with a nucleophile such as a substituted amine to affordthe intermediate X₂ which is then deprotected under the appropriateconditions. R₂ is as defined above, and can be R′₂. R₃ is as definedabove.

In Route 6 shown above, the core indazole structure is formed in anannulation of a 2-halo-5-nitrophenyl aryl ketone Y1 with hydrazine toprovide the requisite 3-aryl-5-nitroindazole Y2. Subsequent protectionand reduction provides the amine Y4. As described for Route 2,diazotization, treatment of the diazonium salt with KI, followed by Pdcatalyzed coupling of the iodo intermediate with an aryl boronic acidaffords the protected 3,5-bisarylindazole intermediate Y6. Standarddeprotection then yields the final products. R₁ and R₂ are as definedabove, and can be R′₁ and R′₂.

The preparation of specific preferred compounds of the invention isdescribed in detail in the following examples. The artisan willrecognize that the chemical reactions described may be readily adaptedto prepare a number of other kinase inhibitors of the invention. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by changing to other suitable reagents known in the art, or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius and all parts andpercentages are by weight. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd.and were used without further purification unless otherwise indicated.Tetrahydrofuran (THF) distilled from calcium hydride and N,N-dimethylformamide (DMF) were purchased from Aldrich in Sure sealbottles and used as received. All solvents were purified using standardmethods readily known to those skilled in the art, unless otherwiseindicated.

The reactions set forth below were done generally under a positivepressure of argon or with a drying tube, at ambient temperature (unlessotherwise stated), in anhydrous solvents, and the reaction flasks werefitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried. Analytical thinlayer chromatography (TLC) was performed on glass-backed silica gel 60 F254 plates Analtech (0.25 mm) and eluted with the appropriate solventratios (v/v), and are denoted where appropriate. The reactions wereassayed by TLC and terminated as judged by the consumption of startingmaterial.

Visualization of the TLC plates was done with a p-anisaldehyde sprayreagent or phosphomolybdic acid reagent (Aldrich Chemical 20 wt % inethanol) and activated with heat. Work-ups were typically done bydoubling the reaction volume with the reaction solvent or extractionsolvent and then washing with the indicated aqueous solutions using 25%by volume of the extraction volume unless otherwise indicated. Productsolutions were dried over anhydrous Na₂SO₄ or MgSO₄ prior to filtrationand evaporation of the solvents under reduced pressure on a rotaryevaporator and noted as solvents removed in vacuo. Flash columnchromatography (Still et al., J. Org. Chem., 43, 2923 (1978)) was doneusing Baker grade flash silica gel (47-61 μm) and a silica gel: crudematerial ratio of about 20:1 to 50:1 unless otherwise stated.Hydrogenation was done at the pressure indicated in the examples or atambient pressure.

¹H-NMR spectra were recorded on a Bruker instrument operating at 300 MHzor 500 MHz and ¹³C-NMR spectra were recorded operating at 75 MHz. NMRspectra were obtained as CDCl₃ solutions (reported in ppm), usingchloroform as the reference standard (7.25 ppm and 77.00 ppm) or CD₃OD(3.4 ppm and 4.8 ppm and 49.3 ppm), or internal tetramethylsilane (0.00ppm) when appropriate. Other NMR solvents were used as needed. When peakmultiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd(doublet of doublets), dt (doublet of triplets). Coupling constants,when given, are reported in Hertz (Hz).

Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR Spectrometeras neat oils, or as KBr pellets, and when given are reported in wavenumbers (cm⁻¹). The mass spectra were obtained using LSIMS orelectrospray. All melting points (mp) are uncorrected.

The starting materials used in the examples are commercially availableand/or can be prepared by techniques known in the art.

EXAMPLE 1 5-Phenyl-3-Styryl-1H-Indazole

(a) Intermediate 1a—5-Chloro-3-iodo-1H-indazole

5-Amino-1H-indazole (15.41 g, 116 mmol) was suspended in a mixture ofwater (250 mL), ice (250 mL), and concentrated HCl (100 mL). The mixturewas cooled in an ice-salt bath to an internal temperature of −5° C. Tothis mixture, was added a solution of sodium nitrite (8.78 g, 127 mmol)in water (75 mL), which had been cooled to 0° C. The resulting diazoniumsolution was stirred for 15 minutes at −5° C. A solution of copper (I)chloride (14.9 g, 151 mmol) in concentrated HCl (150 mL) was cooled to0° C. and then added to the diazonium solution dropwise, causing anorange precipitate to form. The cooling bath was removed to allow thereaction to warm to room temperature. Gas evolution began at 10° C.internal temperature. After stirring at room temperature for 1.5 hours,the gas evolution subsided. The flask was then heated to 60° C. for 30minutes, then cooled to ˜15° C. A brown precipitate formed. Theprecipitate was collected by suction filtration and dried in a vacuumdessicator over NaOH for 16 hours to give crude 5-chloro-1H-indazole(25.6 g) as a tan powder.

This crude intermediate was dissolved in 1,4-dioxane (400 mL). 3 MAqueous NaOH (400 mL) and iodine flakes (35.3 g, 139 mmol) were added tothe solution. After stirring at room temperature for 2 hours, thereaction mixture was neutralized to pH=6 with 20% aqueous citric acid,causing the dark color to change to light green. Saturated aqueoussodium thiosulfate (˜400 mL) was added to the solution, causing thecolor to change from green to yellow, and the solution extracted withethyl acetate (3×1000 mL). The combined organic extracts were dried oversodium sulfate, suction filtered through a coarse frit, and concentratedto a green sludge which was then redissolved in ethyl acetate (500 mL),filtered through a Celite pad, and concentrated to a green solid.Purification by silica gel chromatography (25% ethyl acetate in hexanes)yielded 5-Chloro-3-iodo-1H-indazole 1a (14.18 g, 44% from5-amino-1H-indazole) as an off-white solid: mp=198-199° C.; R_(f)=0.53(50% ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ7.44 (m, 2H), 7.60 (d,1H, J=8.7 Hz), 13.68 (s, 1H). Anal. (C₇H₄ClIN₂) C, H, N.

(b) Intermediate1b—5-Chloro-3-iodo-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

5-Chloro-3-iodo-1H-indazole 1a (8.86 g, 31.8 mmol) was dissolved in THF(100 mL) and cooled in an ice-salt bath to 0° C. Solid sodium t-butoxide(3.67 g, 38.2 mmol) was added, and the mixture stirred at 0° C. for 1hour. 2-(Trimethylsilyl)ethoxymethyl chloride (7.96 g, 38.2 mmol) wasthen added, and stirring continued at 0° C. for 1 hour more. Thesolution was diluted with ethyl acetate (200 mL), washed with water (100mL), and brine (100 mL). The organic layer was dried over magnesiumsulfate, filtered, and concentrated. Silica gel chromatography (5 to 20%ethyl acetate in hexanes) afforded 1b (9.75 g, 75%) as a yellow oil:Rf_(f)=0.39 (5% ethyl acetate/hexanes); ¹H NMR (CDCl₃) δ−0.06 (s, 9H),0.87 (t, 2H, J=8.1 Hz), 3.55 (t, 2H, J=8.1 Hz), 5.70 (s, 2H), 7.43 (dd,1H, J=8.9, 1.7 Hz), 7.49 (m, 2H). Anal. (C₁₃H₁₈ClIN₂OSi) C, H, N.

(c) Intermediate1c—5-Chloro-3-styryl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

5-Chloro-3-iodo-2-SEM-indazole 1b (553 mg, 1.35 mmol), styryl boronicacid (300 mg, 2.03 mmol), and tetrakis(triphenylphosphine) palladium(78.2 mg, 0.068 mmol) were dissolved in toluene (10 mL) and methanol(1.4 mL). Saturated aqueous sodium bicarbonate solution (1.7 mL) wasadded, and the mixture heated in a 90° C. oilbath for 3 hours. Slightrefluxing was observed. After cooling to room temperature, the solutionwas diluted with water (15 mL) and extracted with ethyl acetate (4×50mL). The combined organic extracts were dried over magnesium sulfate,filtered, and concentrated. Purification by silica gel chromatography(toluene) gave pure 1c (350.7 mg, 67%) as a yellow oil: R_(f)=0.20(toluene); ¹H NMR (CDCl₃) δ−0.09 (s, 9H), 0.86 (t, 2H, J=8.1 Hz), 3.55(t, 2H, J=8.3 Hz), 5.65 (s, 2H), 7.2-7.4 (m, 7H), 7.54 (d, 2H, J=7.6Hz), 7.93 (d, 1H, J=1.6 Hz). ¹³C NMR (CDCl₃) δ−1.5, 17.7, 66.5, 77.9,111.0, 119.2, 120.3, 123.6, 126.5, 127.3, 127.4, 128.0, 128.7, 131.6,136.9, 139.4, 142.5. Anal. (C₂₁H₂₅ClN₂OSi.0.02 CHCl₃) C, H, N, Cl.

(d) Intermediate1d—5-Phenyl-3-styryl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

To a solution of 5-chloro-3-styryl-2-SEM-indazole 1c (209.4 mg, 0.544mmol) in dry 1,4-dioxane (0.5 mL) was added phenyl boronic acid (69.6mg, 0.571 mmol), cesium carbonate (213 mg, 0.653 mmol), andtris(dibenzylidineacetone)dipalladium (10.0 mg, 0.0108 mmol). A solutionof tri-tert-butyl phosphine in 1,4-dioxane (0.1 M, 0.217 mL) was added,and the mixture heated to 80° C. for 6 hours. After cooling to roomtemperature, the solution was diluted with ethyl ether (20 mL), andfiltered through a Celite pad to remove the black palladium precipitate.The filtrate was dried over magnesium sulfate, filtered, concentrated,and purified by silica gel chromatography (toluene) to give 1d (77.2 mg,33%) as a colorless oil: R_(f)=0.09 (toluene); ¹H NMR (CDCl₃) δ−0.04 (s,9H), 0.93 (t, 2H, J=8.1 Hz), 3.62 (t, 2H, J=8.1 Hz), 5.76 (s, 2H, J,7.3-7.7 (m, 14H) 8.17 (s, 1H). Anal. (C₂₇H₃₀N₂OSi.0.2H₂O) C, H, N.

(e) Example 1—5-Phenyl-3-Styryl-1H-Indazole

Intermediate 1d (68.1 mg, 0.16 mmol) was dissolved in absolute ethanol(2.0 mL) and 3 M HCl (2.0 mL). The solution was heated to reflux for 20hours, cooled to room temperature, and extracted with ethyl acetate(3×30 mL). The combined organic extracts were dried over magnesiumsulfate, filtered, concentrated, and purified by silica gelchromatography (25 to 50% ethyl acetate in hexanes), affording the titlecompound (19.2 mg, 40%) as a white solid: R_(f)=0.14 (25% ethylacetate/hexanes); ¹H NMR (CDCl₃) δ6.92 (d, 1H, J=6.3 Hz), 7.3-7.7 (m,13H), 8.20 (s, 1H), 10.3 (br s, 1H). HRMS calculated forC₂₁H₁₇N₂297.1392 (MH⁺), found 297.1398. Anal. (C₂₁H₁₆N₂.0.7 H₂O) C, H,N.

EXAMPLE 2 3,5-Distyryl-1H-Indazole

(a) Intermediate 2a—5-Iodo-1H-indazole

5-Amino-1H-indazole (10.21 g, 76.7 mmol) was suspended in a mixture ofwater (100 mL), ice (100 mL), and concentrated HCl (35 mL). The mixturewas cooled in an ice-salt bath to an internal temperature of −5° C. Tothis mixture was added a solution of sodium nitrite (5.82 g, 84.4 mmol)in water (30 mL), which had been cooled to 0° C. The resulting diazoniumsolution was stirred for 10 minutes at −5° C., then a solution ofpotassium iodide (15.3 g, 92 mmol) in water (50 mL) was added slowlydropwise. Significant foaming occurred with the first few drops of Klsolution, and then a black, tarry gum formed. After the addition wascompleted, the mixture was heated to 90° C. for 1 hour. The tarryprecipitate dissolved and purple vapor was evolved during heating. Thereaction was then cooled to room temperature, causing a fine brownprecipitate to form. This precipitate was collected by suctionfiltration, and dried under vacuum to give 5-iodoindazole 2a (14.12 g,75%) as a brown powder: R_(f)=0.28 (50% ethyl acetate/hexanes); ¹H NMR(DMSO-d₆) δ7.40 (d, 1H, J=9.0 Hz), 7.56 (dd, 1H, J=8.5, 1.5 Hz), 8.01(s, 1H) 8.16 (s, 1H), 13.23 (s, 1H). Anal. (C₇H₅IN₂) C, H, I, N.

(b) Intermediate 2b—3,5-Iodo-1H-indazole

Intermediate 2b was prepared by a synthetic method analogous tointermediate 1a synthesis. Treatment of intermediate 2a with iodine andsodium hydroxide yielded 3,5-diiodo-1H-indazole 2b (84%) as a yellowsolid: R_(f)=0.39 (30% ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ7.41(d, 1H, J=8.7 Hz), 7.66 (dd, 1H, J=8.7, 1.5 Hz), 7.77 (d, 1H, J=0.9 Hz)13.65 (s, 1H).

(c) Intermediate2c—3,5-Diiodo-1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-indazole

By a synthetic method similar to intermediate 1b, treatment of3,5-diiodoindazole 2b with sodium t-butoxide and2-(trimethylsilyl)ethoxymethyl chloride afforded 2c (64%) as a yellowoil: R_(f)=0.53 (30% ethyl acetate/hexanes); ¹H NMR (CDCl₃) δ−0.05 (s,9H), 0.86 (t, 2H, J=8.1 Hz), 3.54 (t, 2H, J=8.1 Hz), 5.69 (s, 2H), 7.34(d, 1H, J=8.7 Hz), 7.69 (dd, 1H, J=8.7, 1.5 Hz), 7.87 (d, 1H, J=1.5

(d) Intermediate2d—3,5Distyryl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

Styryl boronic acid (186 mg, 1.26 mmol) was added to a solution of 2c(210.0 mg, 0.42 mmol) and tetrakis(triphenylphosphine)palladium (48.5mg, 0.042 mmol) in toluene (3.5 mL) and methanol (0.5 mL). Saturatedaqueous sodium bicarbonate solution (1.05 mL) was added, and the mixtureheated in a 90° C. oilbath (slight reflux) for 4 hours. After cooling toroom temperature, the reaction was poured into water (15 mL) andextracted with ethyl acetate (4×50 mL). The combined organic extractswere dried over magnesium sulfate, filtered, concentrated, and purifiedby silica gel chromatography (toluene), to give 2d (170.9 mg, 90%) as ayellow oil: R_(f)=0.10 (toluene); ¹H NMR (CDCl₃) δ0.01 (s, 9H), 0.98 (t,2H, J=8.5 Hz), 3.67 (t, 2H, J=8.5 Hz), 5.73 (s, 2H), 7.17 (d, 1H, J=16Hz), 7.3-7.7 (m, 15H), 8.05 (s, 1H). ¹³C NMR (CDCl₃) δ−1.5, 17.6, 66.4,77.7, 110.1, 119.4, 119.8, 123.3, 125.1, 126.3, 126.5, 127.8, 128.6,128.7, 128.9, 131.3, 137.1, 137.3, 140.6, 143.3. Anal.(C₂₉H₃₂N₂OSi.0.1CHCl₃) C, H, N.

(e) Example 2—3,5-Distyryl-1H-Indazole

Example 2 was prepared analogous to example 1, by treatment of 2d with3M HCl which afforded 3,5-distyryl-1H-indazole (33%) as a bright yellowsolid: R_(f)=0.11 (25% ethyl acetate/hexanes); ¹H NMR (CDCl₃) δ7.2-7.7(m, 16H) 8.076 (s, 1H), 10.05 (br s, 1H). HRMS calculated for C₂₃H₁₉N₂323.1548 (MH⁺), found 323.1552. Anal. (C₂₃H₁₈N₂.0.5 H₂O) C, H, N.

EXAMPLE 3 3-(1H-Benzoimidazol-2-yl)-5-Phenyl-1H-Indazole

(a) Intermediate 3a—1-[2-(Trimethylsilanyl)-ethoxymethyl]-1Hbenzoimidazole

(See Whitten et. al., J. Org. Chem. 51, 1891 (1986) incorporated hereinby reference, for a similar procedure): Solid 1H-benzoimidazole (30 g,254 mmol) was added in small portions to a suspension of sodium hydride(10.2 g of 60% dispersion in mineral oil, 254 mmol) in DMF (350 mL) atroom temperature. The mixture was stirred for 3 hours, and then cooledto 0° C. in an ice bath. 2-(Trimethylsilyl)ethoxymethyl chloride (46.57g, 279 mmol) was added dropwise over 10 minutes. The reaction wasstirred for 16 hours, warming to room temperature as the ice bathmelted, then poured into water (1 L), and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate,filtered, concentrated, and purified by silica gel chromatography (50 to85% ethyl acetate in hexanes) to give 3a (56.63 g, 90%) as an amber oil:R_(f)=0.40 (50% ethyl acetate/hexanes); ¹H NMR (CDCl₃) δ−0.04 (s, 9H),0.90 (t, 2H, J=8.1 Hz), 3.50 (t, 2H, J=8.1 Hz), 5.53 (s, 2H), 7.31 (m,2H), 7.54 (m, 1H), 7.81 (m, 1H), 7.96 (s, 1H). Anal. (C₁₃H₂₀N₂OSi.0.5H₂O) C, H, N.

(b) Intermediate3b—2-Iodo-1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-benzoimidazole

A solution of N-SEM-benzimidazole (intermediate 3a) (19.19 g, 77.25mmol) in dry ethyl ether (150 mL) and cooled to −78 ° C. in a dryice/acetone bath, was added dropwise via cannula to a solution ofn-butyllithium (46 mL of 2.5 M in hexanes, 116 mmol) in dry ethyl ether(150 mL), also cooled to −78° C. in a dry ice/acetone bath. Addition ofthe benzimidazole solution took 10 minutes. Stirring was continued 15minutes longer, during which time a dark red color developed. Theresulting aryllithium solution was added dropwise via cannula to asolution of iodine flakes (49 g, 193 mmol) in dry ether (500 mL), itselfcooled to −78° C. in a dry ice/acetone bath. After the addition wascomplete (10 minutes), the cooling bath was removed, and the reactionmixture was allowed to warm for 30 minutes to an internal temperature of−10° C. Water (250 mL) was added, and the mixture was washed withsaturated aqueous sodium bisulfite solution (2×200 mL). The organiclayer was dried over sodium sulfate, filtered, concentrated, andpurified by silica gel chromatography to give 3-iodo-n-SEM-benzimidazole3b (22.84 g, 80%) as a yellow solid: mp=60-63° C.; R_(f) =0.70 (ethylacetate); ¹H NMR (CDCl₃) δ−0.04 (s, 9H), 0.92 (t, 2H, J=8.1 Hz), 3.58(t, 2H, J=8.1 Hz), 5.53 (s, 2H), 7.27 (m, 2H), 7.51 (m, 1H), 7.73 (m,1H). HRMS calculated for C₁₃H₁₉IN₂OSiNa 397.0209 (MNa⁺), found 397.0204.Anal. (C₁₃H₁₉IN₂OSi) C, H, I, N.

(c) Intermediate3c—5-Chloro-1-[2-(trimethylsilanyl)-ethoxymethyl]-3-(trimethylstannyl)-1H-indazole

A mixture of intermediate 1b (6.25 g, 15.3 mmol), hexamethylditin (10.2g, 30.5 mmol), and bis(triphenylphosphine)palladium(II)dibromide (242mg, 0.306 mmol) in toluene (50 mL) was heated to reflux for 30 minutes,then cooled, filtered, and concentrated. Purification by silica gelchromatography (5 to 50% ethyl acetate in hexanes) gave 3c (6.34 g, 93%)as a slightly yellow oil: R_(f)=0.21 (5% ethyl acetate/hexanes),R_(f)=0.23 (toluene); ¹H NMR (CDCl₃) δ−0.06 (s, 9H), 0.56 (s with smallside bands, 9H), 0.87 (t, 2H, J=8.4 Hz), 3.54 (t, 2H, J=8.4 Hz), 5.75(s, 2H), 7.34 (dd, 1H, J=8.7, 1.8 Hz), 7.51 (d, 1H, J=8.7 Hz), 7.66 (d,1H, J=1.8 Hz). Anal. (C₁₆H₂₇CIN₂OSiSn) C, H, Cl, N

(d) Intermediate3d—5-Chloro-1-[2-(trimethylsilanyl)-ethoxymethyl]-3-{1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole

A mixture of 3c (4.47 g, 10.03 mmol), 3b (4.12 g, 11.03 mmol),tetrakis(triphenylphosphine)palladium(0) (579 mg, 0.50 mmol), andcopper(I) iodide (190 mg, 1.00 mmol) in THF (100 mL) was heated toreflux for 1 hour. Additional catalyst (580 mg, 0.50 mmol) and CuI (200mg, 1.05 mmol) were added, and refluxing continued for 20 hours. Aftercooling to room temperature, the black precipitate was filtered off, thefiltrate concentrated, and the residue purified by silica gelchromatography (toluene) to give pure 3d (2.29 g, 43%) as a colorlessoil which crystallizes on standing: mp=80-82° C.; R_(f)=0.12 (10% ethylacetate/hexanes), R_(f)=0.13 (toluene); ¹H NMR (CDCl₃) δ−0.15 (s, 9H),−0.06 (s, 9H), 0.85 (t, 2H, J=8.1 Hz), 0.91 (t, 2H, J=8.4 Hz), 3.60 (t,2H, J=8.4 Hz), 3.61 (t, 2H, J=8.1 Hz), 5.80 (s, 2H, J=8.1 Hz), 6.24 (s,2H), 7.36 (m, 2H), 7.47 (dd, 1H, J=9.0, 2.1 Hz), 7.57 (d, 1H, J=9.0)7.62 (m, 1H), 7.91 (m, 1H), 8.73 (d, 1H, J=2.1 Hz). Anal.(C₂₆H₃₇CIN₄O₂Si₂) C, H, Cl, N.

(e) Intermediate3e—5-Phenyl-1-[2-(trimethylsilanyl)-ethoxymethyl]-3-{1-[2(trimethylsilanyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole

A mixture of 3d (192.0 mg, 0.363 mmol), phenylboronic acid (66.4 mg,0.544 mmol), palladium(II) acetate (3.3 mg, 0.0145 mmol), CyMAP-1 (SeeOld et. al., J. Am. Chem. Soc., 120, 9722 (1998) for a similarprocedure) (5.7 mg, 0.0145 mmol), and cesium fluoride (165 mg, 1.09mmol) in 1,4-dioxane (3.6 mL) was heated in a 100° C. oilbath for 1hour. After cooling to room temperature, the mixture was diluted withethyl acetate (20 mL) and filtered to remove the black precipitate. Thefiltrate was washed with 1M aqueous sodium hydroxide (20 mL), dried overmagnesium sulfate, concentrated, and purified by silica gelchromatography (0 to 4% methanol in dichloromethane) to give 3e (107.0mg, 52%) as a slightly yellow oil: R_(f)=0.26 (dichloromethane); ¹H NMR(CDCl₃) δ−0.15 (s, 9H), −0.04 (s, 9H), 0.86 (t, 2H, J=8.1 Hz), 0.95 (t,2H, J=8.1 Hz), 3.61 (t, 2H, J=8.1 Hz), 3.66 (t, 2H, J=8.1 Hz), 5.85 (s,2H), 6.28 (s, 2H), 7.37 (m, 3H), 7.49 (t, 2H, J=7.5 Hz), 7.63-7.80 (m,5H), 7.91 (m, 1H), 8.88 (s, 1H). Anal. (C₃₂H₄₂N₄O₂Si₂.0.4H₂O) C, H, N.

EXAMPLE 3 3-(1H-Benzoimidazol-2-yl)-5-phenyl-1H-indazole

Tetrabutylammonium fluoride (1.0 M in THF, 3.16 mL) and1,2-diaminoethane (95 mg, 1.58 mmol) were added to intermediate 3e (90.2mg, 0.158 mmol). The solution was heated in a 70° C. oilbath for 20hours, then heated to reflux for 24 hours longer. After cooling to roomtemperature, the solution was diluted with ethyl acetate (30 mL) andwashed with saturated aqueous sodium bicarbonate solution (20 mL). Theorganic layer was dried over magnesium sulfate, filtered, concentrated,and purified by silica gel chromatography (25 to 50% ethyl acetate inhexanes) to give 3-(1H-Benzoimidazol-2-yl)-5-Phenyl-1H-Indazole 3 (33.9mg, 69%) as a white solid: R_(f)=0.30 (50% ethyl acetate/hexanes); ¹HNMR (CDCl₃) δ7.21 (quintet of d, 2H, J=5.7, 1.5 Hz), 7.39 (t, 1H, J=7.4Hz), 7.53 (t, 3H, J=7.5 Hz), 7.76 (m, 5H), 8.71 (s, 1H), 13.01 (s, 1H),13.70 (s, 1H). HRMS calculated for C₂₀H₁₅N₄ 311.1297 (MH⁺), found311.1283.

EXAMPLE 4 3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-phenol

(a) Intermediate4a—5-(3-Methoxyphenyl)-1-[2-(trimethylsilanyl)-ethoxymethyl]-3-{1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole

A mixture of intermediate 3d (371.5 mg, 0.702 mmol),3-methoxyphenylboronic acid (160 mg, 1.05 mmol), palladium(II) acetate(7.9 mg, 0.0355 mmol), CyMAP-1 (See Old et. al., J. Am. Chem. Soc., 120,9722 (1998), incorporated herein by reference, for a similar procedure)(14 mg, 0.0355 mmol), and cesium fluoride (320 mg, 2.11 mmol) in1,4-dioxane (7.1 mL) was heated in a 90° C. oilbath for 22 hours. Aftercooling to room temperature, the mixture was diluted with ethyl acetate(50 mL) and filtered to remove the black precipitate. The filtrate wasdried over magnesium sulfate, concentrated, and purified by silica gelchromatography (10% ethyl acetate in hexanes) to give 4a (178.3 mg, 42%)as a slightly yellow oil: R_(f)=0.20 (10% ethyl acetate/hexanes); ¹H NMR(CDCl₃) δ−0.14 (s, 9H), −0.03 (s, 9H), 0.86 (t, 2H, J=8.1 Hz), 0.95 (t,2H, J=8.1 Hz), 3.61 (t, 2H, J=8.1 Hz), 3.66 (t, 2H, J=8.1 Hz), 3.91 (s,3H), 5.85 (s, 2H), 6.27 (s, 2H), 6.93 (ddd, 1H, J=1.1, 2.5, 8.1 Hz),7.27-7.40 (m, 5H), 7.63-7.70 (m, 2H), 7.77 (dd, 1H, J=1.5, 8.7 Hz), 7.93(m, 1H) 8.87 (s, 1H). Anal. (C₃₃H₄₄N₄O₃Si₂) C, H, N.

(b) Example 4—3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-phenol

A solution of intermediate 4a (88.3 mg, 0.147 mmol) in1,2-dichloroethane (3.0 mL) was treated with boron tribromide-methylsulfide complex (1.0 M in dichloromethane, 0.588 mL) and heated toreflux for 1 hour. Stirring was continued at room temperature for 16hours. Water (5.0 mL) was added, and stirring continued for 30 minutesat room temperature. The mixture was diluted with diethyl ether (30 mL),and washed with saturated aqueous sodium bicarbonate solution (20 mL).The organic layer was washed with 1 M NaOH (3×30 mL). The combinedaqueous washes were acidified to pH=1 with 6 M HCl and extractedsequentially with ether (30 mL), ethyl acetate (30 mL), anddichloromethane (2×20 mL). These organic extracts were combined, driedover magnesium sulfate, filtered, concentrated, and purified by silicagel chromatography (50 to 75% ethyl acetate in hexanes) to give thephenol 4 (11.6 mg, 24%) as a white powder: ¹H NMR (DMSO-d₆) δ6.78 (dd,1H, J=1.9, 7.7 Hz), 7.12-7.27 (m, 4H), 7.31 (t, 1H, J=7.7 Hz), 7.52 (dd,1H, J=2.1, 6.6 Hz), 7.71 (d, 2H, J=1.1 Hz), 7.76 (dd, 1H, J=1.5, 6.8Hz), 8.67 (s, 1H), 9.57 (s, 1H), 13.00 (s, 1H), 13.68 (s, 1H). HRMScalculated for C₂₀H₁₅N₄O 327.1246 (MH⁺), found 327.1231.

EXAMPLE 5 3-(1H-Benzoimidazol-2-yl)-5-(3-methoxyphenyl)-1H-indazole

(a) Example 5—3-(1H-Benzoimidazol-2-yl)-5-(3-methoxyphenyl)-1H-indazole

The same crude reaction mixture from which example 4 was obtained alsoyielded the methoxyphenyl analog 5 as follows:

A solution of intermediate 4a (88.3 mg, 0.147 mmol) in1,2-dichloroethane (3.0 mL) was treated with boron tribromide-methylsulfide complex (1.0 M in dichloromethane, 0.588 mL) and heated toreflux for 1 hour. Stirring was then continued at room temperature for16 hours. Water (5.0 mL) was added, and stirring continued for 30minutes at room temperature. The mixture was diluted with diethyl ether(30 mL), and washed with saturated aqueous sodium bicarbonate solution(20 mL). The organic layer was washed with 1 M NaOH (3×30 mL). Theorganic layer was then dried, filtered, concentrated, and purified bysilica gel chromatography (50 to 75% ethyl acetate in hexanes) to give 5(9.3 mg, 19%) as a white powder: ¹H NMR (DMSO-d₆) δ3.86 (s, 3H), 6.98(dd, 1H, J=2.1, 7.8 Hz), 7.19-7.23 (m, 3H), 7.30 (d, 1H, J=7.8 Hz), 7.45(t, 1H, J=7.8 Hz), 7.52 (dd, 1H, J=1.8, 5.7 Hz), 7.75 (m, 3H), 8.70 (s,1H), 13.00 (s, 1H), 13.70 (s, 1H). HRMS calculated for C₂₁H₁₆N₄ONa363.1222 (MNa⁺), found 363.1225.

EXAMPLE 6 3-(1H-Benzoimidazol-2-yl)-5-(2-fluorophenyl)-1H-Indazole

(a) Intermediate6a—5-(2-Fluorophenyl)-1-[2-(trimethylsilanyl)-ethoxymethyl]-3-{1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole

A mixture of intermediate 3d (419.0 mg, 0.792 mmol),2-fluorophenylboronic acid (166 mg, 1.19 mmol), palladium(II) acetate(9.0 mg,0.04 mmol), CyMAP-1 (See Old et. al., J. Am. Chem. Soc., 120,9722 (1998) incorporated herein by reference, for a similar procedure)(16 mg, 0.04 mmol), and cesium fluoride (361 mg, 2.38 mmol) in1,4-dioxane (8.0 mL) was heated in a 70° C. oilbath for 1 hour. As onlypartial conversion was observed, more palladium (II) acetate (12 mg,0.05 mmol) and CyMAP-1 (14 mg, 0.035 mmol) were added, and stirringcontinued at 70° C. for 16 hr. After cooling to room temperature, themixture was diluted with ethyl acetate (50 mL) and filtered to removethe black precipitate. The filtrate was dried over magnesium sulfate,concentrated, and purified by silica gel chromatography (10% ethylacetate in hexanes) to give 6a (155.6 mg, 43%) as a colorless oil: ¹HNMR (CDCl₃) δ−0.14 (s, 9H), −0.03 (s, 9H), 0.86 (t, 2H, J=8.1 Hz), 0.95(t, 2H, J=8.1 Hz), 3.61 (t, 2H, J=8.1 Hz), 3.66 (t, 2H, J=8.1 Hz), 5.86(s, 2H), 6.27 (s, 2H), 7.15-7.39 (m, 5H), 7.57-7.75 (m, 4H), 7.88 (m,1H) 8.82 (s, 1H). Anal. (C₃₂H₄₁FN₄O₂Si₂.0.4H₂O) C, H, N.

(b) Example 6 —3-(1H-Benzoimidazol-2-yl)-5-(2-fluorophenyl)-1H-indazole

Example 6 was prepared by a synthetic method analogous to example 3.Treatment of intermediate 6a with tetrabutylammonium fluoride afforded 6(21.2 mg, 18%) as a white powder: R_(f)=0.35 (50% ethylacetate/hexanes); ¹H NMR (DMSO-d₆) δ7.20 (m, 2H), 7.33-7.52 (m, 4H),7.62 (m, 2H), 7.74 (m, 2H), 8.65 (s, 1H), 13.02 (s, 1H), 13.75 (s, 1H).HRMS calculated for C₂₀H₁₄FN₄ 329.1202 (MH⁺), found 329.1212. Anal.(C₂₀H₁₃FN₄.1.1H₂O) C, H, N.

EXAMPLE 7 3-(1H-Benzoimidazol-2-yl)-5-(4-methoxyphenyl)-1H-indazole

(a) Intermediate7a′—5-Iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

Intermediate 7a′ was prepared from 5-nitroindazole (Acros organics, adivision of Fisher Scientific, Pittsburg, Pa.) in five steps accordingto the method used to prepare6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1 Hindazolefrom 6-nitroindazole (Found in: Kania, Braganza, et al., patentapplication “Compounds and Pharmaceutical Compositions for InhibitingProtein Kinases, and Methods for Their Use”, p. 52, line 10 to p. 53,line 26; and p.59, line 16 to p. 60, line 4, U.S. Provisional Serial No.60/142,130, filed Jul. 2, 1999, incorporated by reference herein in itsentirety.): ¹H NMR (CDCl₃) δ−0.06 (s, 9H), 0.89 (t, 2H, J=8.4 Hz), 3.57(t, 2H, J=15 8.4 Hz), 5.70 (s, 2H), 7.29-7.44 (m, 6H), 7.59 (d, 2H,J=7.0 Hz), 7.67 (dd, 1H, J=8.7, 1.5 Hz), 8.36 (s, 1H).

(b) Intermediate7b′—5-Iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde

Ozone was bubbled into a solution of 5-iodo-3-styryl-2-SEM-indazole 7a′(4.93 g, 10.35 mmol) in dichloromethane (500 mL) at −78° C. After 20minutes the solution color had changed from orange to deep blue. Themixture was purged with Argon for 30 minutes to remove excess ozone,then dimethylsulfide (1.29 g, 20.7 mmol) was added. The cooling bath wasremoved, and stirring continued until the internal temperature reached15° C., about 2 hours. The solution was washed with water (2×200 mL),dried over magnesium sulfate, filtered and concentrated. Purification bysilica gel chromatography (10% ethyl acetate in hexanes) affordedaldehyde 7b′ (2.74 g, 66%) as a yellow oil: ¹H NMR (CDCl₃) δ−0.05 (s,9H), 0.89 (t, 2H, J=8.4 Hz), 3.56 (t, 2H, J=8.4 Hz), 5.79 (s, 2H), 7.43(d, 1H, J=8.7 Hz), 7.76 (dd, 1H, J=8.8, 1.5 Hz), 8.71 (s, 1H), 10.22 (s,1H).

(c) Intermediate7c′—3-(1H-Benzoimidazol-2-yl)-5-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

To a solution of aldehyde 7b′ (2.74 g, 6.81 mmol) in DMF (130 mL) wereadded 1,2-phenylenediamine (0.74 g, 6.81 mmol) and elemental sulfur(0.26 g, 8.2 mmol). The mixture was heated in a 95° C. oilbath for 14.5hours, cooled to room temperature, and diluted with ethyl acetate (500mL). The solution was washed with a mixture of saturated aqueous sodiumchloride (100 mL) and water (100 mL). The organic layer was then washedwith saturated aqueous sodium bicarbonate (100 mL), followed by water(100 mL), dried over magnesium sulfate, filtered, concentrated, andpurified by silica gel chromatography (20% ethyl acetate in hexanes) togive impure 7c′ as a pale yellow solid. Precipitation fromchloroform/hexanes afforded pure 7c′ (2.15 g, 64%) as a white powder:R_(f)=0.23 (20% ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ−0.12 (s, 9H),0.82 (t, 2H, J=7.9 Hz), 3.59 (t, 2H, J=7.9 Hz), 5.87 (s, 2H), 7.23 (m,2H), 7.52 (d, 1H, J=7.2 Hz), 7.73-7.84 (m, 3H), 8.94 (s, 1H), 13.13 (s,1H). HRMS calculated for C₂₀H₂₃IN₄Osi 491.0759 (MH⁺), found 491.0738.

(d) Intermediate7d′—3-(1H-Benzoimidazol-2-yl)-5-(4-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

2M aqueous sodium carbonate solution (6.4 mL) was added to a solution of7c′ (2.50 g, 5.10 mmol), 4-methoxyphenyl boronic acid (1.01 g, 6.63mmol), and tetrakis(triphenylphosphine)palladium (0.59 g, 0.51 mmol) in1,4-dioxane (35 mL) and methanol (15 mL). The mixture was heated toreflux for 5 hours, then cooled and partitioned between ethyl acetate(300 mL) and a mixture of saturated aqueous sodium chloride (100 mL) andwater (100 mL). The organic layer was dried over magnesium sulfate,filtered, concentrated, and purified by silica gel chromatography (20%ethyl acetate in hexanes) to give a dark brown solid. Precipitation fromdichloromethane/hexanes afforded pure 7d′ (948.6 mg, 40%) as a whitepowder: R_(f)=0.13 (20% ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ−0.10(s, 9H), 0.85 (t, 2H, J=7.9 Hz), 3.63 (t, 2H, J=7.9 Hz), 3.82 (s, 3H),5.91 (s, 2H), 7.10 (d, 2H, J=8.7 Hz), 7.23 (m, 2H), 7.43 (m, 1H), 7.54(d, 1H, J=6.8 Hz), 7.69 (d, 2H, J=8.7 Hz), 7.80 (m, 1H), 7.92 (d, 1H,J=8.9 Hz), 8.70 (s, 1H), 13.08 (s, 1H).

(e) Example7′—3-(1H-Benzoimidazol-2-yl)-5-(4-methoxy-phenyl)-1H-indazole

A solution of intermediate 7d′ (148.4 mg, 0.315 mmol) in ethyl acetate(15 mL) at −78° C. was treated with boron tribromide (1.0 M indichloromethane, 4.73 mL). The solution was stirred for 17 hours,allowing the mixture to gradually warm to room temperature. Water (10mL) was added, and the mixture allowed to stir at room temperature for 6days. The solution was treated with 3M sodium hydroxide solution tobring the pH to 10, then extracted with ethyl acetate (3×20 mL). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated. Purification by silica gel chromatography (50% ethylacetate in hexanes) afforded 7′ (60.5 mg, 56%) as a white solid:R_(f)=0.21 (50% ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ3.82 (s, 3H),7.08 (d, 2H, J=8.9 Hz), 7.21 (m, 2H), 7.53-7.78 (m, 6H), 8.66 (s, 1H),12.96 (s, 1H), 13.63 (s, 1H). Anal. (C₂₁H₁₆N₄O.0.25CH₂Cl₂) C, H, N.

EXAMPLE 8′ 4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-phenol

A mixture of anisole 7′ (44.6 mg, 0.131 mmol) and pyridine hydrochloride(912 mg, 7.9 mmol) was heated in a 180° C. oilbath for 3 hours. Thepyridine salt is liquid at this temperature. After cooling to roomtemperature, the mixture was partitioned between ethyl acetate (20 mL)and saturated aqueous sodium bicarbonate (15 mL). The aqueous layer wasfurther extracted with ethyl acetate (3×20 mL). The combined organicextracts were dried over magnesium sulfate, filtered, concentrated andpurified by silica gel chromatography (50% ethyl acetate/hexanes) togive pure phenol 8′ (29.4 mg, 69%) as a pale yellow solid: R_(f)=0.23(60% ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ6.91 (d, 2H, J=8.4 Hz),7.21 (m, 2H), 7.53 (m, 3H), 7.68 (s, 2H), 7.75 (d, 1H, J=6.9 Hz), 8.61(s, 1H), 9.53 (s, 1H), 12.98 (s, 1H), 13.63 (s, 1H). HRMS calculated forC₂₀H₁₄N₄O 327.1246 (MH⁺), found 327.1253. Anal. (C₂₀H₁₃N₄O.0.8 DMSO) C,H, N.

EXAMPLE 9′3-(1H-Benzoimidazol-2-yl)-5-(3-methoxy-2-methyl-phenyl)-1H-indazole

(a) Intermediate 9a′—3-Methoxy-2-methyl-phenylamine

A suspension of 2-methyl-3-nitroanisole (Aldrich Chemicals) (8.87 g, 53mmol) and 10% palladium on carbon (800 mg) in ethanol (400 mL) wasshaken under 40 psi hydrogen for 1 hour. After filtration through aCelite pad, the solution was concentrated and purified by silica gelchromatography (30% ethyl acetate in hexanes) to give aniline 9a′ (6.94g, 95%) as a slightly orange oil: R_(f)=0.20 (25% ethylacetate/hexanes); ¹H NMR (DMSO-d₆) δ1.88 (s, 3H), 3.68 (s, 3H), 4.74 (brs, 2H), 6.17 (d, 1H, J=8.1 Hz), 6.26 (d, 1H, J=8.1 Hz), 6.81 (t, 1H,J=8.1 Hz). Anal. (C₈H₁₁NO) C, H, N.

(b) Intermediate 9b′—1-Iodo-3-methoxy-2-methyl-benzene

3-Methoxy-2-methyl-phenylamine (5.28 g, 38.5 mmol) was diazotizedaccording to the method of DeGraw, et al. [DeGraw, J. I.; Brown, V. H.;Colwell, W. T.; Morrison, N. E., J. Med. Chem., 17, 762 (1974)],incorporated herein by reference, affording aryl iodide 9b′ (4.17 g,44%) as a yellow oil:: R_(f)=0.53 (10% ethyl acetate/hexanes); ¹H NMR(CDCl₃) δ2.36 (s, 3H), 3.80 (s, 3H), 6.81 (m, 2H), 7.42 (dd, 1 H, J=7.5,1.5 Hz).

(c) Intermediate9c′—2-(3-Methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

1-Iodo-3-methoxy-2-methyl-benzene (3.80 g, 15.3 mmol),Bis(pinacolato)diboron (4.28 g, 16.8 mmol), potassium acetate (4.51 g,46.0 mmol), and1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (625 mg, 0.766mmol) were dissolved in DMSO (70 mL) and heated to 80° C. internaltemperature for 1 hour. After cooling, the mixture was diluted withtoluene (400 mL), washed with water (2×100 mL), dried over magnesiumsulfate, filtered, and concentrated. Purification by silica gelchromatography (5 to 20% ethyl acetate in hexanes) yielded boronic ester9c′ (19.6 g, 52%) as a white, crystalline solid: R_(f)=0.27 (5% ethylacetate/hexanes); ¹H NMR (CDCl₃) δ1.34 (s, 12H), 2.42 (s, 3H), 3.81 (s,3H), 6.91 (d, 1H, J=8.1 Hz), 7.14 (t, 1H, J=7.8 Hz), 7.34 (d, 1H, J=7.5Hz). Anal. (C₁₄H₂₁BO₃) C, H.

(d) Intermediate9d′—4(1H-Benzoimidazol-2-yl)-5-(3-methoxy-2-methyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

Aqueous sodium carbonate solution (2M, 2.65 mL) was added to a solutionof 7c′ (519.4 mg, 1.06 mmol), boronic ester 9c′ (262.8 mg, 1.06 mmol),and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (43.2 mg,0.053 mmol) in DMF (12 mL). The mixture was heated in a 75° C. oilbathfor 4.5 hours, then cooled and partitioned between ethyl acetate (100mL) and a mixture of saturated aqueous sodium chloride (50 mL) and water(50 mL). The organic layer was dried over magnesium sulfate, filtered,concentrated, but ¹H NMR of this crude material showed only 60%conversion. The crude mixture was redissolved in DMF (12 mL) andadditional boronic ester (253 mg, 1.01 mmol), catalyst (140 mg, 0.17mmol), and sodium carbonate solution (2.65 mL) were added. Stirring wascontinued at 80° C. for 15.5 hours. After the same workup as above,crude ¹H NMR showed less than 5% 7c′ remaining. Purification by silicagel chromatography (10 to 30% ethyl acetate in hexanes) afforded 9d′(410.7 mg, 80%) as a white foam: R_(f)=0.37 (30% ethyl acetate/hexanes,same as 7c′); ¹H NMR (DMSO-d₆) δ−0.10 (s, 9H), 0.85 (t, 2H, J=7.9 Hz),2.06 (s, 3H), 3.64 (t, 2H, J=7.9 Hz), 3.85 (s, 3H), 5.92 (s, 2H), 6.92(d, 1H, J=7.2 Hz), 7.02 (d, 1H, J=8.3 Hz), 7.17-7.30 (m, 3H), 7.47-7.53(m, 2H), 7.70 (d, 1H, J=7.7 Hz), 7.90 (d, 1H, J=8.7 Hz), 8.45 (s, 1H),13.09 (s, 1H). Anal. (C₂₈H₃₂N₄O₂Si.0.3H₂O) C, H, N.

(e) Example9′—3-(1H-Benzoimidazol-2-yl)-5-(3-methoxy-2-methyl-phenyl)-1H-indazole

In an analogous manner to example 3, treatment of intermediate 9d′ withtetrabutylammonium fluoride afforded 9′ (47.2 mg, 30%) as a whitepowder: R_(f)=0.23 (5% methanol/dichloromethane); ¹H NMR (DMSO-d₆) δ2.07(s, 3H), 3.85 (s, 3H), 6.91 (d, 1H, J=7.4 Hz), 7.01 (d, 1H, J=8.1 Hz),7.24 (m, 3H), 7.39 (dd, 1H, J=8.7, 1.5 Hz), 7.50 (m, 1H), 7.68 (d, 2H,J=8.5 Hz), 8.40 (s, 1H), 12.96 (s, 1H), 13.66 (s, 1H). Anal.(C₂₂H₁₈N₄O.0.3H₂O) C, H, N.

EXAMPLE 10′3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methyl-phenol

Phenol 10′ was prepared by a synthetic method analogous to phenol 8′, bytreatment of 9′ (31.6 mg, 0.089 mmol) with pyridine hydrochlorideyielded phenol 10′ (20.8 mg, 70%) as an off-white solid: R_(f)=0.21 (60%ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ2.04 (s, 3H), 6.75 (d, 1H,J=7.0 Hz), 6.85 (d, 1H, J=7.7 Hz), 7.08 (t, 1H, J=7.7 Hz), 7.19 (quint,2H, J=7.7 Hz), 7.39 (dd, 1H, J=8.7, 1.5 Hz), 7.50 (d, 1H J=7.5 Hz), 7.68(m, 2H), 8.39 (s, 1H), 9.39 (s, 1H), 12.95 (s, 1H), 13.64 (s, 1H). HRMScalculated for C₂₁H₁₆N₄O 341.1402 (MH⁺), found 341.1410. Anal.(C₂₁H₁₆N₄O.1.0MeOH) C, H, N.

EXAMPLE 11 5-(2-Methylphenyl)-3-phenyl-1H-indazole

(a) Intermediate 11a -5-Nitro-3-phenyl-1H-indazole

To a solution of 2-chloro-5-nitrobenzophenone (15 g, 57 mmol) in ethanol(300 mL) was added hydrazine monohydrate (50 mL, 1 mol). The resultantsolution was stirred overnight (16 hrs.) at ambient temperature, thenpoured into water (2L) and stirred for an additional 2 hours. Theprecipitate that formed was collected by filtration, washed with water(2×100 mL) and air dried to give 5-Nitro-3-phenyl-1H-indazole 11a (13.1g, 80%) as a yellow solid: ¹H NMR (DMSO-d₆) 67 7.48 (tt, 1H, J=1.3, 7.4Hz), 7.58 (dd, 2H, J=7.1, 7.4 Hz), 7.78 (d, 1H, J=9.2 Hz), 8.01 (dd, 2H,J=1.3, 7.1 Hz), 8.25 (dd, 1H, J=2.1, 9.2 Hz), 8.91 (d, 1H, J=2.1 Hz),13.88 (s, 1H). Anal. (C₁₃H₉N₃O₂) C, H, N.

(b) Intermediate11b—5-Nitro-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

Diisopropylethylamine (15 mL, 86.1 mmol) was added, dropwise, to asolution of 5-nitro-3-phenyl-1H-indazole 11a (13 g, 54.3 mmol) and2-(trimethylsilyl)ethoxymethyl chloride (15 g, 90 mmol) in acetonitrile(400 mL). The resultant reaction mixture was stirred at ambienttemperature for 2 hours, then poured into water (1 L) and extracted withethyl acetate (3×300 mL). The combined organic extracts were dried oversodium sulfate and concentrated. The residue obtained was dissolved intoluene (40 mL). To this solution were added2-(trimethylsilyl)ethoxymethyl chloride (3 mL, 17 mmol),tetrabutylammonium bromide (500 mg) and silica (40 g). This mixture wasstirred overnight at ambient temperature, then filtered. The filtratewas subsequently concentrated. Silica gel chromatography (5% ethylacetate/hexanes) provided 11b (15 g, 75%) as a yellow solid: ¹H NMR(DMSO-d₆) δ−0.11 (s, 9H), 0.83 (t, 2H, J=7.9 Hz), 3.62 (t, 2H, J=7.9Hz), 5.91 (s, 2H), 7.52 (tt, 1H, J=0.7, 7.4 Hz), 7.60 (dd, 2H, J=7.1,7.4 Hz), 8.00 (d, 1H, J=9.2 Hz), 8.02 (dd, 2H, J=0.7, 7.1 Hz), 8.35 (dd,1H, J=2.1, 9.2 Hz), 8.91 (d, 1H, J=2.1 Hz).

(c) Intermediate11c—5-Amino-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

A mixture of5-nitro-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole 11b(14 g, 37.9 mmol) and 10% palladium on carbon (1 g) in ethyl acetate(500 mL) was stirred under an atmosphere of hydrogen overnight. Thereaction mixture was filtered through celite, then concentrated toprovide 11c (12.2 g, 95%) as a white solid: ¹H NMR (DMSO-d₆) δ−0.12 (s,9H), 0.80 (t, 2H, J=8.0 Hz), 3.54 (t, 2H, J=8.0 Hz), 5.01 (br s, 2H),5.67 (s, 2H), 6.89 (dd, 1H, J=1.8, 8.8 Hz), 7.12 (d, 1H, J=1.8 Hz) 7.37(tt, 1H, J=0.5, 7.4 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.50 (dd, 2H, J=7.2,7.4 Hz), 7.87 (dd, 2H, J=0.5, 7.2 Hz).

(d) Intermediate11d—5-Iodo-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

Intermediate 11c (12 g, 35.3 mmol) was dissolved in a mixture of aceticacid (300 mL) and water (50 mL). The mixture was cooled in an ice-saltbath to −5° C. To this mixture was slowly added a solution of sodiumnitrite (4.5 g, 65.2 mmol) in water (10 mL) at such a rate to maintainthe reaction temperature below 3° C. The resultant diazonium solutionwas stirred at 0° C. for 20 minutes. A solution of potassium iodide (6.5g, 39.2 mmol) in water (10 mL) was then slowly added to the reaction,again at a rate to maintain the reaction temperature below 3° C. Thereaction was left stirring overnight, gradually equilibrating to roomtemperature. The crude reaction mixture was poured into water (300 mL)and extracted with ethyl acetate (2×500 mL). The combined organicextracts were dried over sodium sulfate and concentrated. Silica gelchromatography (5% ethyl acetate/hexanes) provided 11d (4 g, 25%) as ayellow oil: ¹H NMR (DMSO-d₆) δ−0.12 (s, 9H), 0.83 (t, 2H, J=7.9 Hz),3.57 (t, 2H, J=7.9 Hz), 5.80 (s, 2H), 7.45 (tt, 1H, J=1.3, 7.5 Hz), 7.54(dd, 2H, J=7.1, 7.5 Hz), 7.67 (d, 1H, J=8.8 Hz), 7.75 (dd, 1H, J=1.5,8.8 Hz), 7.94 (dd, 2H, J=1.3, 7.1 Hz), 8.40 (d, 1H, J=1.5 Hz).

(e) Intermediate 11e—5-(2-Methylphenyl)-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

Aqueous saturated sodium bicarbonate (2 mL) was added to a mixture ofintermediate 11d (130 mg, 0.3 mmol), 2-methylphenylboronic acid (120 mg,0.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.02mmol) in 1,4-dioxane (10 mL). The resultant reaction mixture was heatedin a 90° C. oil bath for 18 hours. After cooling to room temperature,the crude reaction mixture was poured into water (50 mL) and extractedwith ethyl acetate (2×25 mL). The combined organic extracts were driedover sodium sulfate and concentrated. Silica gel chromatography (10%ethyl acetate/hexanes) afforded 11e (100 mg, 84%) as an off-white solid:¹H NMR (DMSO-d₆) δ−0.10 (s, 9H), 0.85 (t, 2H, J=8.0 Hz), 2.24 (s, 3H),3.62 (t, 2H, J=8.0 Hz), 5.85 (s, 2H), 7.29 (m, 4H), 7.42 (tt, 1H, J=1.4,7.4 Hz), 7.47 (dd, 1H, J=1.5, 8.3 Hz), 7.52 (dd, 2H, J=7.1, 7.4 Hz),7.84(d, 1H, J=8.3Hz), 7.93 (d, 1H, J=1.5 Hz), 7.99 (dd, 2H, J=1.4, 7.1Hz).

(f) Example 11—5-(2-Methylphenyl)-3-phenyl-1H-indazole

Tetrabutylammonium fluoride (1.0 M in THF, 2 mL) was added to a solutionof intermediate 11e (100 mg, 0.24 mmol) in tetrahydrofuran (5 mL). Thissolution was heated in a 60° C. oil bath for 18 hours, then poured intowater (25 mL) and extracted with ethyl acetate (2×25 mL). The combinedorganic extracts were dried over sodium sulfate and concentrated. Silicagel chromatography (20% ethyl acetate/hexanes) provided5-(2-methylphenyl)-3-phenyl-1H-indazole 11 (55 mg, 80%) as an off-whitesolid: ¹H NMR (DMSO-d₆) δ2.24 (s, 3H), 7.28 (m, 4H), 7.37 (dd, 1H,J=1.5, 8.6 Hz), 7.38 (tt, 1H, J=1.4, 7.5 Hz), 7.50 (dd, 2H, J=7.1, 7.5Hz), 7.64(d, 1H, J=8.6 Hz), 7.91 (d, 1H, J=1.5 Hz), 7.99 (dd, 2H, J=1.4,7.1 Hz), 13.30 (s, 1H). Anal. (C₂₀H₁₆N₂.0.25H₂O) C, H, N.

EXAMPLE 12 3-Phenyl-5-[2-(trifluormethyl)phenyl]-1H-indazole

(a) Intermediate 12a—3-Phenyl5-[2-(trifluoromethyl)phenyl]-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

12a was prepared by a synthetic method analogous to intermediate 11.Palladium catalyzed coupling of intermediate 11d with2-(trifluoromethyl)phenylboronic acid yielded 12a (48%) as a whitesolid: ¹H NMR (DMSO-d₆) δ−0.12 (s, 9H), 0.87 (t, 2H, J=8.1 Hz), 3.72 (t,2H, J=8.1 Hz), 5.62 (s, 2H),7.32 (m, 1H) 7.38 (tt, 1H, J=0.8, 7.4 Hz),7.48 (dd, 2H, J=7.1, 7.4Hz), 7.51 (m, 1H), 7.63 (dd, 1H, J=7.2, 7.7 Hz),7.66 (dd, H, J=1.6, 8.6 Hz), 7.75(m, 1H), 7.8 (d, 1H, J=8.6 Hz), 7.91(d, 1H, J=1.6 Hz), 7.96 (dd, 2H, J=0.8, 7.1 Hz).

(b) Example 12—3-Phenyl 5-[2-(trifluoromethyl)phenyl]-1H-indazole

12 was prepared similar to example 11. Treatment of 12a withtetrabutylammonium fluoride afforded 3-phenyl5-[2-(trifluoromethyl)phenyl]-1H-indazole 12 (74%) as a white solid: ¹HNMR (DMSO-d₆) δ7.34 (m, 1H), 7.38 (tt, 1H, J=1.3, 7.3 Hz), 7.49 (dd, 2H,J=7.1, 7.3 Hz), 7.52 (m, 1H), 7.62 (dd, 1H, J=7.4, 7.7 Hz), 7.65 (dd,1H, J=1.9, 8.6 Hz), 7.73 (dd, J=7.2, 7.5 Hz), 7.85 (d, 1H, J=8.6 Hz),7.94 (d, 1H, J=1.9 Hz), 7.96 (dd, 2H, J=1.3, 7.1 Hz). Anal. (C₂₀H₁₃N₂F₃.0.1H₂O) C, H, N.

EXAMPLE 13 5-(4-Hydroxy-2-methylphenyl)-3-phenyl-1H-indazole

(a) Intermediate 13a—5-(2-methyl[2-(trimethylsilanyl)ethoxymethoxy]phenyl)-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

13a was prepared similar to intermediate 11e. Palladium catalyzedcoupling of intermediate 11d with(2-methyl-4-[2-(trimethylsilanyl)ethoxymethoxy]phenyl)boronic acidyielded 13a (59%) as a pale yellow foam: ¹H NMR (DMSO-d₆) δ−0.09 (s,9H), 0.00 (s, 9H), 0.85 (t, 2H, J=8.0 Hz), 0.92 (t, 2H, J=8.1 Hz), 2.22(s, 3H), 3.62 (t, 2H, J=8.0 Hz), 3.73 (t, 2H, J=8.1 Hz), 5.25 (s, 2H),5.85 (s, 2H), 6.93 (dd, 1H, J=2.6, 8.3 Hz), 6.98 (d, 1H, J=2.6 Hz), 7.22(d, 1H, J=8.3 Hz), 7.43 (tt, 1H, J=0.9, 7.7 Hz), 7.45 (dd, 1H, J=1.3,8.6 Hz), 7.52 (dd, 2H, J=7.2, 7.7 Hz), 7.82 (d, 1H, J=8.6 Hz), 7.89 (d,1H, J=1.3 Hz), 7.99 (dd, 2H, J=0.9, 7.2 Hz).

(b) Example 13—5-(4-Hydroxy-2-methylphenyl)-3-phenyl-1H-indazole

13 was prepared similar to example 11. Treatment of 13a withtetrabutylammonium fluoride afforded5-(4-hydroxy-2-methylphenyl)-3-phenyl-1H-indazole 13 (75%) as a paleyellow solid: ¹H NMR (DMSO-d₆) δ2.17 (s, 3H), 6.66 (dd, 1H, J=2.3, 8.2Hz), 6.70 (d, 1H, J=2.3 Hz), 7.08 (d, 1H, J=8.2 Hz), 7.32 (dd, 1H,J=1.5, 8.6 Hz), 7.39 (tt, 1H, J=1.4, 7.7 Hz), 7.50 (dd, 2H, J=7.2, 7.7Hz), 7.59 (d, 1H, J=8.6 Hz), 7.83 (d, 1H, J=1.5 Hz), 7.97 (dd, 2H,J=1.4, 7.2 Hz) 9.28 (s, 1H), 13.22 (s, 1H). Anal. (C₂₀H₁₆N₂O.0.8H₂O) C,H, N.

EXAMPLE 14 3-Phenyl-5-(Pyrid-4-yl)-1H-indazole

(a) Intermediate 14a-3-Phenyl-5-(pyrid-4-yl)-1-[2-trimethylsilanyl)ethoxymethyl]-1H-indazole

14a was prepared similar to example 11e. Palladium catalyzed coupling ofintermediate 11d with pyridine-4-lboronic acid yielded 14a (76%) as awhite solid: ¹H NMR (DMSO-d₆) δ−0.11 (s, 9H), 0.84 (t, 2H, J=7.9 Hz),3.62 (t, 2H, J=7.9 Hz), (s, 2H), 7.46 (tt, 1H, J=1.1, 7.4 Hz), 7.51 (d,1H, J=8.3 Hz), 7.56 (dd, 2H, J=7.1, 7.4Hz), 7.80 (dd, 1H, J=1.4, 8.3Hz), 7.85 (dd, 2H, J=1.6, 4.5 Hz), 8.07 (dd, 2H, J=1.1, 7.1 Hz), 8.41(d, 1H, J=1.4 Hz), 8.64 (dd, 2H, J=1.6, 4.5 Hz).

(b) Example 14—3-Phenyl 5-(pyrid-4-yl)-1H-indazole

14 was prepared similar to example 11. Treatment of 14a withtetrabutylammonium fluoride afforded 3-phenyl-5-(pyrid-4-yl)-1H-indazole14 (85%) as a white solid: ¹H NMR (DMSO-d₆) δ7.43 (tt, 1H, J=1.2, 7.6Hz), 7.54 (dd, 2H, J=7.1, 7.6Hz), 7.72 (d, 1H, J=8.8 Hz), 7.83 (dd, 2H,J=1.6, 4.5 Hz), 7.84 (dd, 1H, J=1.5, 8.8 Hz), 8.07 (dd, 2H, J=1.2, 7.1Hz), 8.40 (d, 1H, J=1.5 Hz), 8.63 (dd, 2H, J=1.6, 4.5 Hz) 13.39 (s, 1H).Anal. (C₁₈H₁₃N₃.0.2H₂O) C, H, N.

Example 14b—3-Phenyl-5-(Pyrid-3-yl)-1H-indazole

(a) Intermediate 14b′—3phenyl-5-(pyrid-3-yl)-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

14b′ was prepared similar to intermediate 11e. Palladium catalyzedcoupling of intermediate 11d with pyridine-3-boronic acid yielded 14b′(66%) as a white solid: ¹H NMR (DMSO-d₆) δ−0.1 0 (s, 9H), 0.83 (t, 2H,J=7.9 Hz), 3.63 (t, 2H, J=7.9 Hz), 5.86 (s, 2H),7.43 (tt, 1H, J=1.2, 7.5Hz), 7.51 (dd, 1H, J=4.7, 8.0 Hz), 7.54 (dd, 2H, J=7.1, 7.5 Hz), 7.65(d, 1H, J=8.6 Hz), 7.73 (dd, 1H, J=1.5, 8.6 Hz), 8.07 (dd, 2H, J=1.2,7.1 Hz), 8.18 (ddd, 1H, J=1.6, 2.3, 8.0 Hz), 8.32 (d, 1H, J=1.5 Hz),8.56 (dd, 1H, J=1.6, 4.7 Hz), 8.90 (d, 1H, J=2.3 Hz).

(b) Example 14b—3-Phenyl 5-(pyrid-3-yl)-1H-indazole

Similar to example 11, treatment of 14b′ with tetrabutylammoniumfluoride afforded 3-phenyl-5-(pyrid-3-yl)-1-H-indazole 14b (79%) as awhite solid: : ¹H NMR (DMSO-d₆) δ7.41 (tt, 1H, J=1.3, 7.4 Hz), 7.49 (dd,1H, J=4.7, 7.9 Hz), 7.53 (dd, 2H, J=7.1, 7.4 Hz), 7.70 (d, 1H, J=8.7Hz), 7.76 (dd, 1H, J=1.5, 8.7 Hz), 8.08 (dd, 2H, J=1.3, 7.1 Hz), 8.17(ddd, 1H, J=1.7, 2.0, 7.9 Hz), 8.31 (d, 1H, J=1.5 Hz) 8.56 (dd, 1H,J=1.7, 4.7 Hz), 8.99 (d, 1H, J=2.0 Hz), 13.35 (s, 1H). Anal. (C₁₈H₁₃N₃)C, H, N.

EXAMPLE 15 2-Methyl-3-[3-((E)-styryl)-1H-indazol-5-yl]-phenol

(a) Intermediate15a′—5-(3-Methoxy-2-methyl-phenyl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

Intermediate 15a′ was prepared from 7a′ (571.8 mg, 1.42 mmol) by asynthetic method analogous to 9d′, yielding styryl analog 15a′ (442.5mmol, 66%) as a yellow oil: ¹H NMR (DMSO-d₆) δ−0.10 (s, 9H), 0.83 (t,2H, J=8.1 Hz), 2.07 (s, 3H), 3.58 (t, 2H, J=7.9 Hz), 3.84 (s, 3H), 5.79(s, 2H), 6.91 (d, 1H, J=7.6 Hz), 6.99 (d, 1H, J=8.3 Hz), 7.22-7.41 (m,5H), 7.56 (d, 2H, J=5.1 Hz), 7.70-7.78 (m, 3H), 8.09 (s, 1H).

(b) Intermediate15b′—5-(3-Methoxy-2-methyl-phenyl)-3-((E)-styryl-1H-indazole

15b′ was prepared similar to example 3. Treatment of 15a′ (211.4 mg,0.449 mmol) yielded 15b′ (132.7 mg, 87%) as a white foam: R_(f)=0.38(50% ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ1.98 (s, 3H), 3.84 (s,3H), 6.91 (d, 1H, J=7.5 Hz), 6.98 (d, 1H, J=8.1 Hz), 7.21-7.61 (m, 8H),7.70 (d, 2H, J=7.4 Hz, 8.05 (s, 1H), 13.18 (s, 1H). HRMS calculated forC₂₃H₂₀N₂O 341.1648 (MH⁺), found 341.1638. Anal. (C₂₃H₂₀N₂O.0.2H₂O) C, H,N.

(c) Example 15—2-Methyl-3-[3-((E)-styryl)-1H-indazol-5-yl]-phenol

Phenol 15′ was prepared similar to phenol 8′. Treatment of intermediate15b′ (63.1 mg, 0.185 mmol) with pyridine hydrochloride yielded phenol15′ (39.7 mg, 66%) as an off-white solid: R_(f)=0.24 (50% ethylacetate/hexanes); ¹H NMR (DMSO-d₆) δ2.05 (s, 3H), 6.74 (d, 1H, J=7.5Hz), 6.83 (d, 1H, J=7.9 Hz), 7.05 (t, 1H, J=7.7 Hz), 7.25-7.62 (m, 7H),7.70 (d, 2H, J=7.2 Hz), 8.03 (s, 1H), 9.34 (s, 1H), 13.16 (s, 1H). HRMScalculated for C₂₂H₁₈N₂O 327.1497 (MH⁺), found 327.1487. Anal.(C₂₂H₁₈N₂O.0.5H₂O) C, H, N.

EXAMPLE 16 4-[3-((E)-Styryl)-1H-indazol-5-yl]-isoquinoline

(a) Intermediate 16a-3-((E)-Styryl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

A mixture of 7a′ (2.0 g, 4.2 mmol), bis(pinacolato)diboron (1.17 g, 4.6mmol), potassium acetate (1.24 g, 12.6 mmol) and DMSO (25 mL) wasdegassed under vacuum with argon replacement three times.1,1-Bis(Diphenylphosphino)ferrocenedichloropalladium(II)-CH₂Cl₂ (0.172g, 0.21 mmol) was added and the degassing procedure was repeated. Thereaction was heated to 80° C. for 1 hour and the mixture was poured intowater and extracted with ethyl acetate-hexanes (2:1), washed with brine,dried over MgSO₄, and concentrated. Chromatography on silica 6:1hexanes-Et₂O afforded 1.09 g 16a (55%). ¹H NMR (CDCl₃) δ8.51 (s, 1H),7.88 (d, 1H, J=.4 Hz), 7.64 (d, 1H, J=7.2 Hz), 7.58 (m, 2H), 7.48 (s,1H), 7.41 (m, 3H), 7.31 (m, 1H), 3.59 (t, 2H, J=7.3 Hz), 1.41 (s, 12H),0.91 (t, 2H, J=8.3 Hz), −0.06 (s, 9H). Anal. (C₂₇H₃₇N₂O₃SiB) C, H, N.

(b) Intermediate16b—4-[3-((E)-Styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-isoquinoline

Intermediate 16a (0.218 g, 0.47 mmol), 4-bromoisoquinoline (0.082 g,0.39 mmol) and Na₂CO₃ (0.1 g, 0.95 mol) were combined with 3 mL DME and0.5 mL water and the mixture was degassed and purged with argon.Tetrakis(triphenylphosphino)palladium(O) (0.023 g, 0.02 mmol) was addedand the mixture was again degassed and then heated to reflux under argonfor 15 hours. Aqueous work up as with 16a and chromtagraphy on silica(4:1 hexanes-ethyl acetate) yielded 0.181 g (96%) of 16b.; ¹H NMR(CDCl₃) δ8.59 (s, 1H), 8.13 (m, 2H), 7.97 (d, 1H, J=7.6 Hz), 7.73 (m,3H), 7.58 (m, 3H), 7.50 (d, 2H, J=9.5 Hz), 7.26 (m, 4H), 5.82 (s, 2H),3.68 (t, 2H, J=8.1 Hz), 0.97 (t, 2H, J=8.3 Hz), −0.03 (s, 9H). Anal.(C₃₀H₃₁N₃OSi.0.75 H₂O) C, H, N.

(c) Example 16—4-[3-((E)-Styryl)-1H-indazol-5-yl]-isoquinoline

A solution of 16b (0.17 g, 0.35 mmol) in 3.6 mL of 1 Mtetrabutylammonium fluoride in THF and ethylenediamine (0.475 uL, 0.427g, 7.1 mmol) was heated to reflux for 1 hour. The reaction was dilutedwith ethyl acetate and brought to pH 7 with 0.4 M HCl, washed withbrine, dried over MgSO₄, and concentrated. Chromtagraphy on silica (1:1hexanes-ethyl acetate) yielded 0.079 g (64%) of 16 as a white solid. ¹HNMR (CDCl₃) δ10.20 (br s, 1H), 9.31 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H),8.09 (d, 1H, J=7.2 Hz), 7.93 (d, 1H, J=7.2 Hz), 7.20—7.75 (m, 11H).Anal. (C₂₄H₁₇N₃.0.4 H₂O) C, H, N.

EXAMPLE 17 4-[3-((E)-Styryl)-1H-indazol-5-yl]-quinoline

(a) Intermediate17a—4-[3-((E)-Styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-quinoline

17a was prepared by a synthetic method analogous to intermediate 16b.Employing 4-chloroquinoline, 17a was prepared in 79% yield. ¹H NMR(CDCl₃) δ8.99 (d, 1H, J=4.4 Hz), 8.21 (d, 1H, J=7.9 Hz), 8.15 (s, 1H,),7.95 (d, 1H, J=8.4 Hz), 7.72 (m, 2H), 7.42-7.62 (m, 10H), 5.82 (s, 2H),3.67 (t, 2H, J=9.3 Hz), 0.97 (t, 2H, J=8.3 Hz), −0.02 (s, 9H). Anal.(C₃₀H₃₁N₃OSi.0.5 H₂O) C, H, N.

(b) Example 17—4-[3-((E)-Styryl)-1H-indazol-5-yl]-quinoline

Example 17 was prepared similar to intermediate 16. 17a was deprotectedto afford 17 in 50% yield as a white solid. ¹H NMR (CDCl₃) δ13.10 (br s,1H), 8.98 (d, 1H, J=4.4 Hz), 8.37 (s, 1H), 8.15 (d, 1H, J=8.4 Hz), 8.00(d, 1H, J=8.4 Hz), 7.54-7.79 (m, 9H), 7.37 (m, 2H), 7.26 (m, 1H). Anal.(C₂₄H₁₇N₃.1.0 H₂O) C,

EXAMPLE 18 5-(4-Pyridyl-3-(2-Pyrrolyl)-1H-indazole

(a) Intermediate 18a—2-Fluoro-5-nitrobenzoyl chloride

A solution of 2-chloro-5-nitrobenzoic acid (10.3 g, 56 mmol) in thionylchloride (90 ml, 1.2 mol) was heated at reflux for 2 hours. Excessthionyl chloride was removed by concentration, in vacuo. The residueobtained was dissolved in ether (150 ml), then concentrated to provide2-fluoro-5-nitrobenzoyl chloride 18a (11.21 g, 99%) as an off-whitesolid: ¹H NMR (DMSO-d₆) δ7.62 (dd, 1H, J=9.1, 9.6 Hz), 8.48 (ddd, 1H,J=3.0, 6.9, 9.1 Hz), 8.60 (dd, 1H, J=3.0, 6.3 Hz). Anal. (C₇H₃NO₃CIF) C,H, N, Cl.

(b) Intermediate18b—1-(2-Fluoro-5-nitrophenyl)-1-(1H-pyrrol-2-yl)methanone

A solution of 2-chloro-5-nitrobenzoyl chloride 18a (10.04 g, 49 mmol)and pyrrole (3.4 ml, 3.29 g, 49 mmol) in 1,2-dichloroethane (110 ml) wascooled to 0° C. prior to addition of AlCl₃ (6.61 g, 49.6 mmol) as thesolid. The resultant reaction mixture was stirred overnight, graduallywarming to room temperature. The crude reaction was, subsequently,poured into a mixture of concentrated HCl (20 ml) and ice water (200ml). After stirring for an additional 90 minutes, the layers wereseparated and the aqueous phase was extracted with CH₂Cl₂ (2×200 ml).The combined organic extracts were washed with water (200 ml) andsaturated NaHCO₃ (200 ml), dried over sodium sulfate and concentrated.Silica gel chromatography (25% ethyl acetate/hexanes) provided 18b (7.23g, 63%) as a pale yellow solid: ¹H NMR (DMSO-d₆) δ6.28 (ddd, 1H, J=2.1,2.3, 3.6 Hz), 6.74 (ddd, 1H, J=1.3, 2.3, 2.5 Hz), 7.32 (ddd, 1H, J=1.3,2.4, 3.6 Hz), 7.65 (dd, 1H, J=9.0, 9.1 Hz), 8.39 (dd, 1H, J=3.0, 5.8Hz), 8.45 (ddd, 1H, J=3.0, 4.4, 9.1 Hz), 12.33 (broad, 1H). Anal.(C₁₁H₇N₂O₃F.0.1 HCl) C, H, N.

(c) Intermediate18c—1-(2-Fluoro-5-nitrophenyl)-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyrrol-2-yl)methanone

A solution of 1-(2-fluoro-5-nitrophenyl)-1-(1H-pyrrol-2-yl)methanone 18b(1.72 g, 7.3 mmol) in THF (30 ml) was added dropwise, under an argonatmosphere, to a stirred suspension of NaH (350 mg, 8.75 mmol) in THF(15 ml) at 0° C. This mixture was stirred at 0° C. for 45 minutes priorto addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.70 g, 10.2mmol) in a single portion as the neat liquid. The resultant reactionmixture was stirred at ambient temperature overnight, then poured intosaturated NaHCO₃ (80 ml). The layers were separated and the aqueousphase was extracted with ethyl acetate (2×50 ml). The combined organicextracts were washed with brine (60 ml), dried over sodium sulfate andconcentrated. Silica gel chromatography (10% ethyl acetate/hexanes)provided 18c (2.24 g, 84%) as a yellow syrup: ¹H NMR (DMSO-d₆) δ−0.07(s, 9H), 0.83 (t, 2H, J=7.8 Hz), 3.53 (t, 2H, J=7.8 Hz), 5.74 (s, 2H),6.27 (dd, 1H, J=2.5, 4.0 Hz), 6.75 (dd, 1H, J=1.4, 4.0 Hz), 7.57 (dd,1H, J=1.4, 2.5 Hz), 7.64 (dd, 1H, J=9.0, 9.1 Hz), 8.29 (dd, 1H, J=3.0,5.8 Hz), 8.45 (ddd, 1H, J=3.0, 4.6, 9.1 Hz). Anal. (C₁₇H₂₁N₂O₄FSi) C, H,N.

(d) Intermediate18d—1-(5-Amino-2-fluorophenyl)-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyrrol-2-yl)methanone

A mixture of1-(2-fluoro-5-nitrophenyl)-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyrrol-2-yl)methanone18c (3.63 g, 10 mmol) and 10% palladium on carbon (365 mg) in ethylacetate (90 ml) was stirred under an atmosphere of hydrogen overnight.The reaction mixture was filtered through celite, then concentrated toprovide 18d (3.30 g, 99%) as an amber syrup: ¹H NMR (DMSO-d₆) δ−0.07 (s,9H), 0.82 (t, 2H, J=8.0 Hz), 3.50 (t, 2H, J=8.0 Hz), 5.12 (br s, 2H),5.71 (s, 2H), 6.20 (dd, 1H, J=2.5, 3.9 Hz), 6.59 (dd, 1H, J=2.9, 5.6 Hz)6.60 (dd, 1H, J=1.8, 3.9 Hz), 6.66 (ddd, 1H, J=2.9, 4.3, 8.8 Hz), 6.93(dd, 1H, J=8.8, 9.7 Hz), 7.42 (dd, 1H, J=1.8, 2.5 Hz). Anal.(C₁₇H₂₃N₂O₂FSi) C, H, N.

(e) Intermediate18e—1-(2-Fluoro-5-iodophenyl)-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyrrol-2-yl)methanone

Intermediate 18d (332 mg, 1.0 mmol) was dissolved in a mixture of aceticacid (10 ml) and acetonitrile (10 ml). This vigorously stirred solutionwas cooled in an ice-salt bath to −5° C., prior to addition of asolution of sodium nitrite (83 mg, 1.2 mmol) in water (10 ml). Theresultant diazonium solution was stirred for 45 minutes, graduallywarming to 5° C. The reaction was, again, cooled to −5° C. preceding theaddition of a solution of potassium iodide (232 mg, 1.4 mmol) in water(3 ml). The resultant mixture was stirred for an additional 2 hours,warming to 15° C., then poured into a mixture of K₂CO₃ (30 g) and icewater (100 ml). This aqueous mixture was extracted with ethyl acetate(2×50 ml). The combined organic extracts were washed with 10% aqueousNa₂S₂O₃ (50 ml), dried over sodium sulfate and concentrated. Silica gelchromatography (5% ethyl acetate/hexanes) provided 18e (160 mg, 36%) asa colorless oil: ¹H NMR (DMSO-d₆) δ−0.08 (s, 9H), 0.81 (t, 2H, J=7.9Hz), 3.50 (t, 2H, J=7.9 Hz), 5.71 (s, 2H), 6.24 (dd, 1H, J=2.6, 4.0 Hz),6.63 (dd, 1H, J=1.7, 4.0 Hz) 7.18 (dd, 1H, J=8.7, 9.7 Hz), 7.51 (dd, 1H,J=1.7, 2.6 Hz), 7.74 (dd, 1H, J=2.3, 6.4 Hz), 7.90 (ddd, 1H, J=2.3, 4.9,8.7 Hz). Anal. (C₁₇H₂₁NO₂FSil) C, H, N, I.

(f) Intermediate18f—1-[2-Fluoro-5-(4-pyridyl)phenyl]-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyrrol-2-yl)methanone

Diisopropylethylamine (1.3 ml, 7.5 mmol) was added to a mixture of1-(2-fluoro-5-iodophenyl)-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyrrol-2-yl)methanone18e (798 mg, 1.8 mmol), tetrakis(triphenylphosphine)palladium(0) (65 mg,0.06 mmol) and pyridine-4-boronic acid (323 mg, 2.6 mmol) in DMF (20ml). The resultant reaction mixture was heated in a 90° C. oil bath for18 hours, under an argon atmosphere. After cooling to room temperature,the crude reaction mixture was poured into water (100 ml) and extractedwith ethyl acetate (2×75 ml). The combined organic extracts were washedwith water (6×75 ml), dried over sodium sulfate and concentrated. Silicagel chromatography (20% ethyl acetate/CH₂Cl₂) afforded 18f (407 mg, 57%)as a pale yellow oil: ¹H NMR (DMSO-d₆) δ−0.06 (s, 9H), 0.84 (t, 2H,J=7.9 Hz), 3.54 (t, 2H, J=7.9 Hz), 5.76 (s, 2H), 6.24 (dd, 1H, J=2.6,4.0 Hz), 6.68 (dd, 1H, J=1.8, 4.0 Hz) 7.49 (dd, 1H, J=8.7, 9.3 Hz),7.51(dd, 1H, J=1.8, 2.6 Hz), 7.72 (d, 2H, J=6.2 Hz), 7.87 (dd, 1H,J=2.4, 6.5 Hz), 8.02 (ddd, 1H, J=2.4, 4.9, 8.7 Hz), 8.63 (d, 2H, J=6.2Hz). Anal. (C₂₂H₂₅N₂O₂FSi) C, H, N.

(g) Intermediate18g—5-(4-Pyridyl)-3-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyrrol-2-yl)-1H-indazole

A solution of1-[2-fluoro-5-(4-pyridyl)phenyl]-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyrrol-2-yl)methanone18f (504 mg, 1.3 mmol) and hydrazine monohydrate (1.7 ml, 35 mmol) inethanol (35 ml) was heated at reflux for 42 hours. The ethanol was thenremoved by concentration, in vacuo. The residue obtained was partitionedbetween water (25 ml) and ethyl acetate (25 ml). The layers wereseparated and the aqueous phase was extracted with ethyl acetate (25ml). The combined organic extracts were washed with saturated NaHCO₃ (30ml), dried over sodium sulfate and concentrated. Silica gelchromatography (3% CH₃OH/CH₂Cl₂) provided 18g (430 mg, 87%) as anoff-white solid: ¹H NMR (DMSO-d₆) δ−0.28 (s, 9H), 0.63 (t, 2H, J=8.0Hz), 3.28 (t, 2H, J=8.0 Hz), 5.72 (s, 2H), 6.26 (dd, 1H, J=2.8, 3.5 Hz),6.79 (dd, 1H, J=1.7, 3.5 Hz) 7.10 (dd, 1H, J=1.7, 2.8 Hz), 7.67 (d, 1H,J=8.9 Hz), 7.77 (d, 2H, J=6.2 Hz), 7.81 (dd, 1H, J=1.6, 8.9 Hz), 8.19(d, 1H, J=1.6 Hz), 8.61 (d, 2H, J=6.2 Hz), 13.25 (s, 1H). Anal.(C₂₂H₂₆N₄OSi) C, H, N.

(h) Example 18—5-(4Pyridyl)-3-(2-pyrrolyl)-1H-indazole

Tetrabutylammonium fluoride (1.0 M in THF, 5 ml) was added to a solutionof intermediate 18g (366 mg, 0.9 mmol) and 1,2-diaminoethane (150 mg,2.5 mmol) in tetrahydrofuran (20 ml). This solution was heated at refluxfor 42 hours, then poured into saturated NaHCO₃ (30 ml) and extractedwith ethyl acetate (2×25 ml). The combined organic extracts were driedover sodium sulfate and concentrated. Silica gel chromatography (3%CH₃OH/CH₂Cl₂) provided 5-(4-Pyridyl)-3-(2-pyrrolyl)-1H-indazole 18 (71mg, 29%) as an off-white solid: ¹H NMR (DMSO-d₆) δ6.20 (dd, 1H, J=2.6,5.6 Hz), 6.82-6.92 (m, 2H), 7.64 (d, 1H, J=8.7 Hz), 7.81 (dd, 1H, J=1.4,8.7 Hz), 7.83 (d, 2H, J=6.1 Hz), 8.37 (d, 1H, J=1.4 Hz), 8.62 (d, 2H,J=6.1 Hz), 11.37 (s, 1H), 13.09 (s, 1H). Anal. (C₁₆H₁₂N₄.0.05CH₂Cl₂) C,H, N.

Example 18b′: 5-Nitro3-(2-Pyrrolyl)-1H-indazole

18b′ was prepared similar to intermediate 11a. Treatment of1-(2-fluoro-5-nitrophenyl)-1-(1H-pyrrol-2-yl)methanone 18b withhydrazine hydrate afforded 5-nitro-3-(2-pyrrolyl)-1H-indazole 18b′ (75%)as an orange-red solid: ¹H NMR (DMSO-d₆) δ6.23 (ddd, 1H, J=2.4, 2.6, 3.6Hz), 6.81 (ddd, 1H, J=1.5, 2.5, 3.6 Hz), 6.93 (ddd, 1H, J=1.5, 2.1, 2.6Hz), 7.70 (d, 1H, J=9.2 Hz), 8.21 (dd, 1H, J=2.0, 9.2 Hz), 8.90 (d, 1H,J=2.0 Hz), 11.57 (broad, 1H), 13.62 (s, 1H). Anal. (C₁₁H₈N₄O₂) C, H, N.

EXAMPLE 194-[3-(4-Chloro-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

(a) Intermediate 19a—1H-indazole-3-carboxylic acid methoxy-methylamide

3-Carboxyindazole (100 g, 617 mmol) in 1 L DMF was treated withcarbonyldiimidazole (110 g, 678 mmol) at 25° C. with gas evolution for15 minutes. The reaction was heated to 60-65° C. for 2 hours and thenallowed to cool to 25° C. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678mmol) was added as a solid and the mixture was heated to 65° C. for 3hours The reaction was concentrated to a paste and taken up in 2 LCH₂Cl₂, washed with water, and then 2N HCl. Product was visibly comingout of solution. Solid was filtered and rinsed separately with ethylacetate. The ethyl acetate and CH₂Cl₂ layers were separately washed withNaHCO₃, and brine, dried over MgSO4 and concentrated. The resultingsolids were combined, triturated with a 1:1 mixture of CH₂Cl₂-ether,filtered, and dried to afford 106 g (84%) of intermediate 19a as a whitesolid: R_(f)=0.38 (75% ethyl acetate in hexanes); ¹H NMR (DMSO-d₆)δ13.60 (s, 1H,), 7.80 (d, 1H, J=8.2 Hz), 7.60 (d, 1H, J=8.2 Hz), 7.41(t, 1H, J=8.0 Hz), 7.22 (t, 1H, J=8.0 Hz), 3.77(s, 3H), 3.44 (s, 3H).Anal. (C₁₀H₁₁N₃O₂) C, H, N.

(b) Intermediate 19b—5-Iodo-1H-indazole-3-carboxylic acidmethoxy-methyl-amide

To the amide 19a (20 g, 97.4 mmol) in 1 L CH₂Cl₂ was addedbis(trifluoroacetoxy)iodobenzene (46 g, 107 mmol) followed byportionwise addition of iodine (14.84 g, 58.5 mmol) at 25° C. After 1hour, 600 mL of saturated Na₂HSO₃ was added and a solid began toprecipitate which was filtered and rinsed with excess CH₂Cl₂. Thefiltrate was washed with brine, dried over MgSO₄, concentrated, and theremaining solid triturated with a minimal amount of CH₂Cl₂. The combinedsolids were dried under vacuum over KOH to give 29.26 g (91%) of iodide19b as a pale white solid: R_(f)=0.31 (50% ethyl acetate in hexanes); ¹HNMR (DMSO-d₆) δ13.79 (s, 1H), 8.39 (s, 1H), 7.65 (d, 1H, J=8.7 Hz), 7.48(d, 1H, J=8.7 Hz), 3.76 (s, 3H), 3.44 (s, 3H). Anal. (C₁₀H₁₀N₃IO₂) C, H.

(c) Intermediate19c—5-Iodo-1-(4-methoxy-benzyl)-1H-indazole-3-carboxylic acidmethoxy-methyl-amide

To the iodide 19b (15 g, 45.3 mmol) in 200 mL THF was added NaH (1.9 gof a 60% mineral oil dispersion, 1.14 g, 47.6 mmol), portionwise withgas evolution. After 15 minutes the reaction was cooled to 0° C. andp-methoxybenzyl chloride (8.51 g, 54.4 mmol) was added followed by NaI(679 mg, 4.5 mmol). The mixture was heated to 45° C. for 9h and allowedto cool to 25° C. The solution was diluted with ethyl acetate, washedwith saturated aqueous NH₄Cl, brine and dried over MgSO₄ andconcentrated to a viscous oil. Ether was added to the oil and a solidformed which was filtered and rinsed with ether to provide 14.18 g (70%)of 19c as a faint yellow solid.: R_(f)=0.42 (50% ethyl acetate inhexanes); ¹H NMR (CDCl₃) δ8.60 (s, 1H), 7.56 (dd, 1H, J=8.8, 1.6 Hz),7.11 (m, 3H), 6.80 (dd, 2H, J=6.7, 2.1 Hz), 5.52 (s, 2H), 3.81 (s, 3H),3.75 (s, 3H), 3.51 (s, 3H). Anal. (C₁₈H₁₈N₃O₃I) C, H, N, I.

(d) Intermediate19d—5-Iodo-1-(4-methoxy-benzyl)-1H-indazole-3-carbaldehyde

The amide 19c (12.8 g, 28.3 mmol) in 300 mL THF was cooled to −5° C. andLiAIH₄ (1.29 g, 34 mmol) was added portionwise over 10 minutes. After 30minutes the reaction was quenched by the slow addition of ethyl acetateat −5° C. and the whole was poured into 0.4 N NaHSO₄. The organic layerwas washed with brine, dried over MgSO₄, and concentrated to afford aslightly offwhite solid which was triturated with a minimal amount ofether, filtered, washed with ether, and dried to give 9.79 g (88%) ofaldehyde 19d as a white solid: R_(f)=0.57 (50% ethyl acetate inhexanes); ¹H NMR (CDCl₃) δ10.20 (s, 1H), 8.96 (s, 1H), 7.63 (dd, 1H,J=8.8, 1.6 Hz), 7.18 (m, 3H), 6.83 (d, 1H, J=8.7 Hz), 5.57 (s, 3H), 3.75(s, 3H). Anal. (C₁₆H₁₃N₂O₂I.0.1 ethyl acetate) C, H, N, I.

(e) Intermediate19e—1-(4-Methoxy-benzyl)-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-1H-indazole-3-carbaldehyde

Bis(pinacolato)diboron (Aldrich Chemicals) (7.05 g, 27.8 mmol), iodide19d (9.90 g, 25.24 mmol), potassium acetate (12.4 g, 126 mmol), and1,1′-bis(diphenyl-phosphino)ferrocenedichloropalladium(II) (515 mg,0.631 mmol) were dissolved in dimethysulfoxide (150 mL), degassed, andheated in an 80° C. oilbath for 1 hour. After cooling to roomtemperature, the mixture was partitioned between ethyl acetate (200 mL)and water (150 mL). The organic layer was dried over magnesium sulfate,filtered, concentrated, and purified by silica gel chromatography (25%ethyl acetate in hexanes) to give boronic ester 19e (9.75 g, 98%) as anoff-white solid: R_(f)=0.37 (25% ethyl acetate in hexanes); ¹H NMR(DMSO-d₆) δ1.31 (s, 12H), 3.69 (s, 3H), 5.75 (s, 2H), 6.87 (d, 2H, J=8.7Hz), 7.27 (d, 2H, J=8.7 Hz), 7.74 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=8.4Hz), 8.52 (s, 1H), 10.17 (s, 1H). Anal. (C₂₂H₂₅BN₂O₄) C, H, N.

(f) Intermediate19f—5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazole-3-carbaldehyde

To a degassed solution of boronic ester 19e (6.00 g, 15.30 mmol) and4-bromoisoquinoline (5.17 g, 24.8 mmol) in ethylene glycol dimethylether (DME, 76 mL) was added aqueous sodium carbonate solution (2.0 M,38.2 mL, 76.4 mmol) followed by tetrakis(triphenylphosphine)palladium(0)(883 mg, 0.76 mmol). The mixture was heated in an 80° C. oilbath for 5hours, attaining a maximum internal temperature of 78° C. After coolingto room temperature, the mixture was diluted with ethyl acetate (200mL), washed with water (100 mL), and saturated aqueous sodium chloridesolution (50 mL). The organic extracts were dried over magnesiumsulfate, filtered, concentrated and columned (silica gel, 30 to 70%ethyl acetate in hexanes), affording 19f (3.56 g, 59%) as an off-whitesolid: R_(f)=0.16 (50% ethyl acetate in hexanes); ¹H NMR (DMSO-d₆) δ3.71(s, 3H), 5.83 (s, 2H), 6.92 (d, 2H, J=8.7 Hz), 7.38 (d, 2H, J=8.7 Hz),7.74 (m, 4H), 8.10 (d, 1H, J=8.7 Hz), 8.22 (m, 2H), 8.48 (s, 1H), 9.37(s, 1H), 10.21 (s, 1H).

(g) Intermediate 19g—3-Chloro-benzene-1,2-diamine

A solution of sodium borohydride (1.90 g, 50.2 mmol) in water (40 mL)was added to a suspension of 10% palladium on carbon (250 mg) in water(50 mL) while bubbling argon into the latter solution via pipette. Tothis was added a solution of 3-chloro-2-nitroaniline (AstatechChemicals) (4.33 g, 25.1 mmol) in 2N aqueous sodium hydroxide (125 mL)dropwise via addition funnel, slowly enough to keep gas evolution undercontrol. The mixture was stirred at room temperature for 10 minutes,filtered through a Celite pad, acidified with 3N aqueous hydrochloricacid, and extracted with dichloromethane (3×200 mL). The combinedorganic layers were dried over magnesium sulfate, filtered,concentrated, and purified by silica gel chromatography (1 to 20% ethylacetate in dichloromethane) to give diamine 19g (2.13 g, 60%) as yellowoil: R_(f)=0.30 (dichloromethane); ¹H NMR (DMSO-d₆) δ4.60 (br s, 2H),4.80 (br s, 2H), 6.37 (t, 1H, J=7.8 Hz), 6.48 (m, 2H). Anal. (C₆H₇CIN)C, H, Cl, N.

(h) Intermediate19h—4-[3-(4Chloro-1H-benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-isoquinoline

Aldehyde 19f (405.6 mg, 1.03 mmol) and diamine 19g (147 mg, 1.03 mmol)were condensed in the presence of elemental sulfur (50 mg, 1.55 mmol)analogous to the synthesis of intermediate 7c′, affording intermediate19h (275.5 mg, 52%) as a pale yellow solid: R_(f)=0.12 (50% ethylacetate in hexanes); ¹H NMR (DMSO-d₆) δ3.74 (s, 3H), 5.83 (s, 2H), 6.93(d, 2H, J=8.8 Hz), 7.22 (m, 2H), 7.38 (d, 2H, J=8.5 Hz), 7.48 (d, 1H,J=7.2 Hz), 7.67 (dd, 1H, J=8.7, 1.5 Hz), 7.76 (m, 3H), 8.04 (d, 1H,J=8.7 Hz), 8.26 (dd, 1H, J=7.4, 1.5 Hz), 8.54 (s, 1H), 8.64 (s, 1H),9.40 (s, 1H, 13.41 (s, 1H).

(i) Example19—4-[3-(4Chloro-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

Concentrated sulfuric acid (0.3 mL) was added to a solution of 19h(121.6 mg, 0.236 mmol) in trifluoroacetic acid (3.0 mL), and stirred atroom temperature for 19 hours. The mixture was then diluted with water(50 mL), treated with concentrated aqueous ammonium hydroxide untilpH=8, and extracted with ethyl acetate (3×50 mL). The combined organicextracts were dried over magnesium sulfate, filtered, concentrated, andpurified by silica gel chromatography to give 19 (41.5 mg, 44%) as awhite solid: R_(f)=0.40 (75% ethyl acetate in hexanes); ¹H NMR (DMSO-d₆)[Some peaks are doubled due to tautomeric isomerization] δ7.22 (m, 2H),7.48 (d, 1H, J=7.2 Hz), 7.64 (d, 1H, J=8.7), 7.79 (m, 4H), 8.27 (d, 1H,J=7.5), 8.55 (s, 1H), 8.63 (s, 1H), 9.40 (s, 1H), 13.39 and 13.56 (2 s,1H together), 13.94 (s, 1H). Anal. (C₂₃H₁₄CIN₅.1.2 CH₃OH) C, H, Cl, N.

EXAMPLE 204-{3-[5-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-isoquinoline

(a) Intermediate20a—4-{1-(4-Methoxy-benzyl)-3-[5-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-isoquinoline

A suspension of 5-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine (513.0mg, 2.17 mmol) [See Kim, Jung Sun; et al.; J. Med. Chem.; 39; 992 (1996)for the synthesis of this compound] and 10% palladium on carbon (200.8mg) in ethyl acetate (50 mL) was shaken under 40 psi H₂ for 17 hours.The catalyst was removed by filtration through a Celite pad, and themixture concentrated to afford crude4-(4-Methyl-piperazin-1-yl)-benzene-1,2-diamine (522 mg) as a yellowfoam. This crude diamine was added to a solution of aldehyde 19f (853.7mg, 2.17 mmol) and elemental sulfur (83 mg, 2.60 mmol) in anhydrousdimethylformamide (40 mL), and the solution heated in an 80° C. oilbathfor 6 hours. After cooling to room temperature, the solution was dilutedwith ethyl acetate (150 mL) and washed with water (50 mL) and saturatedaqueous sodium chloride solution (50 mL). The organic layer was driedover magnesium sulfate, filtered, concentrated, and purified by silicagel chromatography (1:20:400 concentrated aqueous NH₄OH: EtOH:CH₂Cl₂),affording 20a (623 mg, 50%) as an orange-brown foam: R_(f)=0.20 (10%ethanol in dichloromethane); ¹H NMR (DMSO-d₆) [Some peaks are doubleddue to tautomeric isomerization] δ2.23 (s, 3H), 2.49 (m, 4H), 3.10 (m,4H), 3.71 (s, 3H), 5.80 (s, 2H), 6.91 (m, 4H), 7.36 and 7.47 (2 d, 3Htogether, J=8.3, 8.7 Hz), 7.64 (d, 1H, J=8.9 Hz), 7.77 (m, 3H), 7.99 (m,1H), 8.25 (d, 1H, J=7.2 Hz), 8.53 (s, 1H), 8.62 (2 s, 1H together), 9.39(s, 1H), 12.78 and 12.83 (2 s, 1H together). Anal. (C₃₆H₃₃N₇O.0.9 H₂O)C, H, N.

(b) Example20—4-{3-[5-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-isoquinoline

Anisole (229.4 mg, 2.12 mmol) was added to a solution of 20a (123.0 mg,0.212mmol) in glacial acetic acid (2.12 mL). Concentrated aqueoushydrobromic acid (2.12 mL) was added, and the mixture heated to refluxfor 21 hours. After cooling, the reaction solution was added dropwise toa rapidly stirred mixture of dichloromethane (50 mL), tetrahydrofuran(20 mL), and saturated aqueous sodium bicarbonate (30 mL). The layerswere separated, and the organic layer was washed with saturated aqueoussodium bicarbonate (20 mL), followed by water (20 mL). The organic layerwas dried over magnesium sulfate, filtered, concentrated, and purifiedby silica gel chromatography (1:20:100 concentrated aqueous NH₄OH:EtOH:CH₂Cl₂), yielding slightly impure 20 (76.0 mg, 78%) as a red foam.Further purification by precipitation from dichloromethane/hexanesafforded pure 20 (47.1 mg, 48%) as a pink solid: R_(f)=0.20 (1:20:50concentrated aqueous NH₄OH: EtOH:CH₂Cl₂); ¹H NMR (DMSO-d₆) [Some peaksare doubled due to tautomeric isomerization] δ2.23 (s, 3H), 2.49 (m,4H), 3.11 (m, 4H), 6.91 (m, 2H), 7.35 and 7.47 (2 d, 1H together, J=9.0,8.9 Hz), 7.61 (d, 1H, J=8.9 Hz), 7.80 (m, 4H), 8.26 (d, 1H, J=7.7 Hz),8.54 (s, 1H), 8.59 and 8.62 (2 s, 1H together), 9.39 (s, 1H), 12.74 and12.79 (2 s, 1H together), 13.73 and 13.76 (2 s, 1H together). Anal.(C₂₈H₂₅N₇.0.7 H₂O) C, H, N.

EXAMPLE 21 2-[5-(3-Hydroxy-2-methyl-phenyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ol

(a) Intermediate 21a—2-[5-Iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ol

Aldehyde 7b′ (2.66 g, 6.62 mmol), and 2,3-diaminophenol (available fromAldrich Chemicals) (822 mg, 6.62 mmol) were condensed in the presence ofelemental sulfur analogous to the synthesis of intermediate 7c′,affording 21a (2.04 g, 61%) as a yellow solid: R_(f)=0.15 (25% ethylacetate in hexanes); ¹H NMR (DMSO-d₆) [Some peaks are doubled due totautomeric isomerization] δ−0.13 (s, 9H), 0.82 (t, 2H, J=8.1 Hz), 3.59(t, 2H, J=7.8 Hz), 5.85 (s, 2H), 6.59 (d, 1H, J=7.5 Hz), 7.01 (m, 2H),7.71 (d, 1H, J=8.7 Hz), 7.81 (dd, 1H, J=8.8, 1.5 Hz), 8.90 and 9.04 (2s, 1H together), 9.49 and 9.74 (2 s, 1H together), 12.69 and 12.96 (2 s,1H together). Anal. (C₂₀H₂₃IN₄O₂Si) C, H, N.

(b) Intermediate21b—2-[5-(3-Methoxy-2-methyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ol

Boronic ester 9c′ (250 mg, 1.01 mmol) and iodide 21a (510.6 mg, 1.01mmol) were coupled by the procedure analogous to intermediate 9d′synthesis, affording 21b (256.7 mg, 51%) as a yellow foam: R_(f)=0.22(30% ethyl acetate in hexanes, co-spots with 21a); ¹H NMR (DMSO-d₆)[Some peaks are doubled due to tautomeric isomerization] δ−0.11 (s, 9H),0.85 (t, 2H, J=8.1 Hz), 2.06 (s, 3H), 3.64 (t, 2H, J=7.7 Hz), 3.85 (s,3H), 5.90 (s, 2H), 6.55 (dd, 1H, J=7.2, 1.1 Hz), 6.96 (m, 4H), 7.26 (t,1H, J=7.9 Hz), 7.46 (dd, 1H, J=8.7, 1.5 Hz), 7.87 (d, 1H, J=8.7 Hz),8.40 and 8.55 (2 s, 1H together), 9.45 and 9.61 (2 s, 1H together),12.62 and 12.91 (2 s, 1H together). Anal. (C₂₈H₃₂N₄O₃Si.0.4 H₂O) C, H,N.

(c) Intermediate21c—2-[5-(3Methoxy-2-methyl-phenyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ol

In an analogous manner to example 3, treatment of 21b (174.5 mg, 0.349mmol) with tetrabutylammonium fluoride afforded 21c (59.8 mg, 46%) as anoff-white solid: R_(f)=0.26 (5% methanol in dichloromethane); ¹H NMR(DMSO-d₆) [Some peaks are doubled due to tautomeric isomerization] δ2.07(s, 3H), 3.85 (s, 3H), 6.53 and 6.62 (2 d, 1H together, J=7.4, 7.7 Hz),6.96 (m, 4H), 7.26 (t, 1H, J=7.9 Hz), 7.37 (d, 1H, J=8.5 Hz), 7.66 (d,1H, J=8.5 Hz), 8.35 and 8.49 (2 s, 1H together), 9.45 and 9.55 (2 s, 1Htogether), 12.53 and 12.78 (2 s, 1H together), 13.57 and 13.62 (2 s, 1Htogether). HRMS calculated for C₂₂H₁₉N₄O₂ 371.1508 (MH⁺), found371.1523.

(d) Example 21—2-[5-(3-Hydroxy-2-methyl-phenyl)-1H-indazol-3-yl]-1H-benzoimidazol-4ol

By a procedure analogous to phenol 8′ synthesis, treatment of 21c (45.9mg, 0.124 mmol) with pyridine hydrochloride afforded 21 (29.0 mg, 66%)as a tan powder: R_(f)=0.28 (10% methanol in dichloromethane); ¹H NMR(DMSO-d₆) [Some peaks are doubled due to tautomeric isomerization] δ2.04(s, 3H), 6.54 and 6.62 (dd and d, 1H together, J=7.2, 1.3 and 7.7 Hz),6.75 (d, 1H, J=7.4 Hz), 6.85 (d, 1H, J=7.9 Hz) 7.01 (m, 3H), 7.37 and7.38 (dd and dd, 1H together, J=8.5, 1.5 Hz for each), 7.65 and 7.66 (2d, 1H together, J=8.7 Hz for each), 8.35 and 8.48 (2 s, 1H together),9.38 and 9.39 (2 s, 1H together), 9.46 and 9.56 (2 s, 1H together),12.52 and 12.77 (2 s, 1H together), 13.55 and 13.60 (2 s, 1H together).HRMS calculated for C₂₁H₁₇N₄O₂ 357.1351 (MH⁺), found 357.1360. Anal.(C₂₁H₁₆N₄O₂.0.8 CH₃OH) C, H, N.

EXAMPLE 226-(3-Hydroxy-propyl)-2-methyl-3-[3-((E)-styryl)-1H-indazol-5-yl]-phenol

(a) Intermediate 22a—3-Amino-2-methyl-phenol

A suspension of 2-methyl-3-nitro-phenol (Aldrich Chemicals) (29.8 g,194.6 mmol) and 10% palladium on carbon (3.01 g) in ethanol (350 mL) wasshaken under 40 psi hydrogen for 3.5 hours. After filtration through aCelite pad, the solution was concentrated and purified by silica gelchromatography (50% ethyl acetate in hexanes) to give aniline 22a (20.32g, 85%) as a colorless solid: R_(f)=0.50 (50% ethyl acetate/hexanes); ¹HNMR (DMSO-d₆) δ1.87 (s, 3H), 4.63 (s, 2H), 6.08 (dd, 2H, J=7.9, 10.5Hz), 6.64 (t, 1H, J=7.9 Hz), 8.76 (s, 1H). Anal. (C₇H₉NO) C, H, N.

(b) Intermediate 22b—3-Iodo-2-methyl-phenol

3-Amino-2-methyl-phenol 22a (18.35 g, 149 mmol) was diazotized accordingto the method of DeGraw, et al. [DeGraw, J. I.; Brown, V. H.; Colwell,W. T.; Morrison, N. E., J. Med. Chem., 17, 762 (1974)]. After columnchromatography (10-50% ethyl acetate in hexanes), aryl iodide 22b (9.06g, 26%) was isolated as an orange solid. Further purification byrecrystallization from hexanes afforded 5.63 g pale orange needles:R_(f)=0.35 (20% ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ2.22 (s, 3H),6.80 (m, 2H), 7.24 (dd, 1H, J=7.5, 1.5 Hz), 9.75 (s, 1H).

(c) Intermediate 22c—1-Allyloxy-3-iodo-2-methyl-benzene

Allyl bromide (1.57 g, 13.0 mmol) was added to a solution of3-iodo-2-methyl phenol (2.026 g, 8.66 mmol) in acetone (18 mL). Thesolution was heated at reflux for 2 hours, then cooled to roomtemperature, diluted with ethyl acetate (50 mL), and acidified with 1Naqueous hydrochloric acid until an aqueous of pH=2 was obtained. Thelayers were separated, and the aqueous layer extracted with ethylacetate (2×10 mL). The combined organic extracts were dried overmagnesium sulfate, filtered, concentrated and purified by silica gelchromatography (5% ethyl acetate in hexanes) to give allyl ether 22c(2.1353 g, 90%) as a yellow oil: R_(f)=0.60 (20% ethyl acetate/hexanes);¹H NMR (CDCl₃) δ2.40 (s, 3H), 4.53 (d of t, 2H, J=5.1, 1.5 Hz), 5.28 (dof q, 1H, J=10.6, 1.5 Hz), 5.42 (d of q, 1H, J=17.3, 1.5 Hz), 6.05 (m,1H), 6.82 (m, 2H), 7.43 (dd, 1H, J=7.2, 1.9 Hz).

(d) Intermediate 22d—6-Allyl-3-iodo-2-methyl-phenol

Intermediate 22c (1.0954 g, 3.996 mmol) was heated in a sealed tube in a200° C. oilbath for 2 hours. After cooling and column chromatography,phenol 22d (767.2 mg, 70%) was obtained as an amber oil: R_(f)=0.31 (10%ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ2.30 (s, 3H), 3.28 (d, 2H,J=6.6 Hz), 5.02 (m, 2H), 5.90 (m, 1H), 6.66 (d, 1H, J=7.9 Hz), 7.26 (d,1H, J=8.1 Hz), 8.63 (s, 1H).

(e) Intermediate 22e—6-(3-Hydroxy-propyl)-3-iodo-2-methyl-phenol

Borane-dimethylsulfide complex (0.159 mL, 1.68 mmol borane) was addeddropwise to a chilled solution (0° C.) of intermediate 22d (459.8 mg,1.677 mmol) in dry ether (5.0 mL). The cooling bath was removed, andstirring continued for 1 hour. Absolute ethanol (2.5 mL) was added,followed by aqueous sodium hydroxide (2.5 N, 3.35 mL). The mixture wasrecooled to 0° C., and hydrogen peroxide added (30 wt % in H₂O, 0.27mL). After stirring at 0° C. for 15 minutes, the cooling bath wasremoved, and the mixture was allowed to warm to room temperature over 1hour. The solution was partitioned between ether (50 mL) and 1N aqueoushydrochloric acid (final aqueous pH˜2-3). The organic layer was driedover magnesium sulfate, filtered, and concentrated to an orange oil.Purification by silica gel chromatography yielded alcohol 22e (353.1 mg,72%) as a yellow oil R_(f)=0.11 (20% ethyl acetate/hexanes); ¹H NMR(DMSO-d₆) δ1.64 (quint, 2H, J=7.0 Hz), 2.29 (s, 3H), 2.54 (t, 2H, J=7.5Hz) 3.39 (t, 2H, J=6.5 Hz), 4.54, (br s, 1H), 6.68 (d, 1H, J=8.1 Hz),7.23 (d, 1H, J=8.1 Hz), 8.58 (s, 1H).

(f) Intermediate22f—6-(3-Hydroxy-propyl)-2-methyl-3-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-phenol

Aqueous sodium carbonate solution (2M, 1.79 mL) was added to a degassedsolution of boronic ester 16a (534.1 mg, 1.12 mmol), aryl iodide 22e(209.1 mg, 0.716 mmol), and1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (29 mg, 0.036mmol) in DMF (3.2 mL). The mixture was heated in an 80° C. oilbath for1.5 hours, 5 then cooled and partitioned between ethyl acetate (50 mL)and water (10 mL). The organic layer was dried over magnesium sulfate,filtered, and concentrated. Purification by silica gel chromatography(20 to 50% ethyl acetate in hexanes) afforded 22f (301.9 mg, 82%) as ayellow foam: R_(f)=0.07 (20% ethyl acetate/hexanes); ¹H NMR (DMSO-d₆)δ−0.09 (s, 9H), 0.83 (t, 2H, J=7.9 Hz), 1.73 (quint, 2H, J=7.5 Hz), 2.09(s, 3H), 2.65 (t, 2H, J=7.5 Hz), 3.46 (t, 2H, J=6.5 Hz), 3.58 (t, 2H,J=8.0 Hz), 5.78 (s, 2H), 6.74 (d, 1H, J=7.7 Hz), 6.98 (d, 1H, J=7.9 Hz),7.27 (m, 1H), 7.37 (m, 3H), 7.56 (m, 2H), 7.73 (m, 3H), 8.06 (s, 1H),8.25 (br s, 1H). Anal. (C₃₁H₃₈N₂O₃Si.0.5 CH₂Cl₂) C, H, N.

(g) Intermediate 22—6-(3-Hydroxy-propyl)-2-methyl-3-[3-((E)-styryl)-1H-indazol-5-yl]-phenol

22 was prepared similar to example example 3, treatment of intermediate22f (202.9 mg, 0.394 mmol) with tetrabutylammonium fluoride afforded 22(34.3 mg, 23%) as a white powder: R_(f)=0.19 (50% ethylacetate/hexanes); ¹H NMR (DMSO-d₆) δ1.72 (quint, 2H, J=7.4 Hz) 2.10 (s,3H), 2.64 (t, 2H, J=7.4 Hz), 3.45 (t, 2H, J=6.2 Hz), 4.59 (br s, 1H),6.74 (d, 1H, J=7.7 Hz), 6.97 (d, 1H, J=7.7 Hz), 7.33 (m, 4H), 7.45 (m,5H), 8.02 (s, 1H), 8.26 (s, 1H), 13.18 (s, 1H). Anal.(C₂₅H₂₄N₂O₂.0.6H₂O) C, H, N.

EXAMPLE 233-[3-(4-Hydroxymethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methyl-phenol

(a) Intermediate 23a—(2-Amino-3-nitro-phenyl)-methanol

3-Nitroanthranilic acid [See Chapman, E. and Stephen, H. J. Chem. Soc.,127, 1791, (1925) for the synthesis of this reagent] (5.00 g, 27.45mmol) was reduced with borane-dimethylsulfide complex according to themethod of Mikelson, et al. [Mickelson, John W.; et al. J. Med. Chem.;39; 4654 (1996)], affording benzyl alcohol 23a (4.27 g, 93%) as anorange crystalline solid: R_(f)=0.22 (75% ethyl acetate in hexanes); ¹HNMR (DMSO-d₆) δ4.50 (d, 2H, J=5.4 Hz), 5.43 (t, 1H, J=5.4 Hz), 6.65 (dd,1H, J=8.7, 7.2 Hz), 7.10 (br s, 2H), 7.47 (d, 1H, J=7.0 Hz), 7.94 (dd,1H, J=8.8, 1.5 Hz). Anal. (C₇H₈N₂O₃) C, H, N.

(b) Intermediate 23b—(2,3-Diamino-phenyl)-methanol

In a manner analogous to the synthesis of 9a′, intermediate 23a (3.16 g,18.8 mmol) was hydrogenated in ethanol (300 mL) to give 23b (2.23 g,86%) as a yellow-brown solid. Further purification by recrystalizationfrom ethanol gave 23b (1.04 g, 40%) as yellow needles: R_(f)=0.17 (75%ethyl acetate in hexanes); ¹H NMR (DMSO-d₆) δ4.36 (br s, 6H), 4.90 (brs, 1H), 6.42 (m, 3H). Anal. (C₇H₁₀N₂O) C, H, N.

(c) Intermediate23c—{2-[5-Iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-yl}-methanol

23c was prepared similar to 7c′ synthesis. Condensation of diamine 23b(587.3 mg, 4.25 mmol) with aldehyde 7b′ (1.71 g, 4.25 mmol) in thepresence of elemental sulfur afforded 23c (1.57 g, 71%) as a yellowsolid: ¹H NMR (DMSO-d₆) [Some peaks are doubled due to tautomericisomerization] δ−0.13 (s, 9H), 0.82 (t, 2H, J=7.7 Hz), 3.58 (t, 2H,J=7.9 Hz), 4.87 (br s, 1H), 5.04 (br s, 1H), 5.22 (br s, 1H), 5.87 (s,2H), 7.26 (m, 2H), 7.39 and 7.67 (m and br s, 1H together), 7.75 (d, 1H,J=8.7 Hz), 7.83 (dd, 1H, J=8.8, 1.5 Hz), 8.95 (d, 1H, J=1.1 Hz), 12.97and 13.13 (2 s, 1H together). Anal. (C₂₁H₂₅IN₄O₂Si) C, H, I, N.

(d) Intermediate23d—2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol

By a synthetic method analogous to 9c′ synthesis, iodide 22b (1.21 g,5.17 mmol) was converted to boronic ester 23d (1.15 g, 95%), a white,crystalline solid: R_(f)=0.18 (10% ethyl acetate in hexanes); ¹H NMR(CDCl₃) δ1.35 (s, 12H), 2.46 (s, 3H), 6.87 (dd, 1H, J=7.9, 1.0 Hz), 7.08(t, 1H, J=7.5 Hz), 7.35 (dd, 1H, J=7.4, 1.1 Hz). Anal. (C₁₃H₁₉BO₃.0.2H₂O) C, H.

(e) Intermediate23e—3-[3-(4-Hydroxymethyl-1H-benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-2-methyl-phenol

23e was prepared similar to 9d′ synthesis. Iodide 23c (276.3 mg, 0.514mmol) and boronic ester 23d (300 mg, 1.28 mmol) were coupled to give 23e(128.2 mg, 50%) as a yellow solid: R_(f)=0.16 (40% ethyl acetate inhexanes); ¹H NMR (DMSO-d₆) [Some peaks are doubled due to tautomericisomerization] δ−0.11 (s, 9H), 0.85 (t, 2H, J=7.9 Hz), 2.03 and 2.07 (2s, 3H together), 3.63 (t, 2H, J=7.7 Hz), 4.87 and 4.97 (2 d, 2Htogether, J=5.8 and 5.5 Hz), 5.11 and 5.25 (2 t, 1H together, J=5.6 and6.1 Hz), 5.92 and 5.93 (2 s, 2H together), 6.76 (dd, 1H, J=7.5, 3.4 Hz),6.86 (d, 1H, J=7.9 Hz), 7.17 (m, 3H), 7.39 and 7.60 (dd and d, 1Htogether, J=6.8, 2.1 and 7.9 Hz), 7.49 (d, 1H, J=8.7 Hz), 7.89 (d, 1H,J=8.9 Hz), 8.44 and 8.47 (2 s, 1H together), 9.46 and 9.48 (2 s, 1Htogether), 12.91 and 13.09 (2 s, 1H together). Anal. (C₂₈H₃₂N₄O₃Si.0.3H₂O) C, H, N.

(f) Example23—3-[3-(4-Hydroxymethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methyl-phenol

23 was prepared similar to example 3. Treatment of 23e (130.7 mg, 0.261mmol) with tetrabutylammonium fluoride afforded 23 (61.6 mg, 64%) as awhite solid: R_(f)=0.22 (70% ethyl acetate in hexanes); ¹H NMR (DMSO-d₆)[Some peaks are doubled due to tautomeric isomerization] δ2.04 and 2.07(2 s, 3H together), 4.86 and 4.97 (2 d, 2H together, J=6.0 and 5.7 Hz),5.10 and 5.23 (2 t, 1H together, J=5.6 and 6.0 Hz), 6.76 (d, 1H, J=7.2Hz), 6.85 (d, 1H, J=8.1 Hz), 7.14 (m, 3H), 7.3 and 7.58 (dd and d, 1Htogether, J=7.2, 1.9 and 7.7 Hz), 7.40 (dd, 1H, J=8.5, 1.5 Hz), 7.67 (d,1H, J=8.1 Hz), 8.39 and 8.42 (2 s, 1H together), 9.43 and 9.45 (2 s, 1Htogether), 12.81 and 12.96 (2 s, 1H together), 13.65 and 13.70 (2 s, 1Htogether). Anal. (C₂₂₄H₁₈N₄O₂.1.0 CH₃OH) C, H, N.

EXAMPLE 24 7-[3-((E)-Styryl)-1H-indazol-5-yl]-isoquinoline

(a) Intermediate 24a—1,1,1-Trifluoro-methanesulfonic acidisoquinolin-7-yl ester

Trifluoromethanesulfonic anhydride (4.54 g, 16.10 mmol) was addeddropwise to a chilled (0° C.) mixture of 7-hydroxyisoquinoline (1.9477g, 13.24 mmol, Lancaster Chemicals) in pyridine (14 mL). Stirring wascontinued at 0° C. for 1 hour, then at room temperature for 24 hours.The solution was partitioned between dichloromethane and saturatedaqueous sodium bicarbonate solution. The organic layer was dried overmagnesium sulfate, filtered, concentrated, and purified by silica gelchromatography (50% ethyl acetate in hexanes) to give triflate 24a (3.27g, 88%) as a pale yellow oil: R_(f)=0.23 (50% ethyl acetate/hexanes); ¹HNMR (DMSO-d₆) δ7.72 (dd, 1H, J=9.0, 2.5 Hz), 7.80 (d, 1H, J=5.8 Hz),8.06 (d, 1H, J=9.0 Hz), 8.23 (d, 1H, J=2.5 Hz), 8.55 (d, 1H, J=5.7 Hz),9.39 (s, 1H). ¹³C NMR (DMSO-d₆) δ118.33 (q, J=320 Hz), 119.35, 119.99,124.17, 128.03, 129.9, 134.31, 144.09, 147.02, 152.46. Anal.(C₁₀H₆F₃NO₃S.0.1H₂O) C, H, N, S.

(b) Intermediate24b—7-[3-((E)-Styryl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]-isoquinoline

Isoquinoline triflate 24a (150 mg, 0.540 mmol) was added to a degassedsolution of boronic ester 16a (282.9 mg, 0.594 mmol), powdered potassiumphosphate (344 mg, 1.62 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (13 mg, 0.016 mmol), and1,1′-bis(diphenylphosphino)ferrocene (9 mg, 0.016 mmol) in 1,4-dioxane(10 mL). The mixture was heated in an 80° C. oilbath for 6 hours, thencooled and partitioned between ethyl acetate (50 mL) and saturatedaqueous sodium chloride solution (25 mL). The organic layer was driedover magnesium sulfate, filtered, and concentrated. Purification bysilica gel chromatography (10 to 75% ethyl acetate in hexanes) afforded24b (92.7 mg, 36%) as a fluorescent pink gel: R_(f)=0.06 (20% ethylacetate/hexanes); ¹H NMR (CDCl₃) δ−0.04 (s, 9H), 0.94 (t, 2H, J=8.4 Hz),3.64 (t, 2H, J=8.1 Hz), 5.79 (s, 2H), 7.30-8.09 (m, 14H), 8.26 (d, 2H,J=12.9 Hz).

(c) Example 24—7-[3-((E)-Styryl)-1H-indazol-5-yl]-isoquinoline

Similar to example 3, treatment of intermediate 24b (86 mg, 0.18 mmol)with tetrabutylammonium fluoride afforded 24 (27.2 mg, 43%) as a whitesolid: R_(f)=0.11 (70% ethyl acetate in hexanes); ¹H NMR (DMSO-d₆) δ7.29(t, 1H, J=7.2 Hz), 7.41 (t, 2H, J=7.2 Hz), 7.66 (m, 5H), 7.88 (t, 2H,J=5.7 Hz), 8.09 (d, 1H, J=8.7 Hz), 8.29 (dd, 1H, J=8.4, 1.8 Hz), 8.51(m, 3H), 9.41 (s, 1H), 13.28 (s, 1H). Anal. (C₂₄H₁₇N₃.0.6 CH₂OH) C, H,N.

EXAMPLE 25 4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

(a) Intermediate25a—3-(1H-Benzoimidazol-2-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazole

By a procedure analogous to boronic ester 19e synthesis, iodide 7c′(2.36 g, 4.81 mmol) was converted to boronic ester 25a (1.43 g, 61%), awhite, crystalline solid: ¹H NMR (DMSO-d₆) δ−0.13 (s, 9H), 0.82 (t, 2H,J=7.7 Hz), 1.35 (s, 12H), 3.59 (t, 2H, J=7.9 Hz), 5.89 (s, 2H), 7.24 (m,2H), 7.53 (m, 1H), 7.83 (m, 3H), 8.95 (s, 1H), 13.15 (s, 1H). Anal.(C₂₆H₃₅BN₄O₃Si) C, H, N.

(b) Intermediate25b—4-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]-isoquinoline

By a procedure analogous to 19f synthesis, 4-bromoisoquinoline (238 mg,1.14 mmol) was coupled with boronic ester 25a (280.4 mg, 0.572 mmol) togive 25b (237.5 mg, 84%) as a white solid: R_(f)=0.20 (50% ethyl acetatein hexanes); ¹H NMR (DMSO-d₆) δ−0.07 (s, 9H), 0.86 (m, 2H), 3.67 (t, 2H,J=7.9 Hz), 5.98 (s, 2H), 7.20 (br m, 2H), 7.55 (br m, 1H), 7.65 (br m,1H), 7.71 (m, 4H), 8.07 (d, 1H, J=8.7 Hz), 8.27 (dd, 1H, J=7.2, 1.7 Hz),8.56 (s, 1H), 8.66 (d, 1H, J=0.8 Hz), 9.41 (s, 1H), 13.17 (s, 1H).

(c) Example25—4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

25 was prepared similar to example 3. Intermediate 25b (152.4 mg, 0.310mmol) was treated with tetrabutylammonium fluoride to give 25 (61.9 mg,55%) as a white foam: R_(f)=0.16 (70% ethyl acetate in hexanes); ¹H NMR(DMSO-d₆) δ7.18 (br m, 2H), 7.56 (br m, 2H), 7.63 (dd, 1H, J=8.5, 1.7Hz), 7.81 (m, 4H), 8.27 (dd, 1H, J=7.4, 1.2 Hz), 8.55 (s, 1H), 8.62 (s,1H), 9.40 (s, 1H), 13.05 (br s, 1H), 13.84 (s, 1H).

EXAMPLE 263-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-6-(3-hydroxy-propyly)-2-methyl-phenol

(a) Intermediate26a—3-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]-6-(3-hydroxy-propyl)-2-methyl-phenol

By a procedure analogous to the synthesis of 25b, boronic ester 25a (303mg, 0.618 mmol) was coupled with iodide 22e (180.5 mg, 0.618 mmol),affording 26a (124.4 mg, 38%) as a white solid: R_(f)=0.30 (50% ethylacetate in hexanes); ¹H NMR (DMSO-d₆) δ−0.11 (s, 9H), 0.85 (t, 2H, J=7.9Hz), 1.74 (quint, 2H, J=7.0 Hz), 2.08 (s, 3H), 2.66 (t, 2H, J=7.7 Hz),3.47 (q, 2H, J=5.3 Hz), 3.63 (t, 2H, J=7.9 Hz), 4.60 (t, 1H, J=5.0 Hz),5.91 (s, 2H), 6.75 (d, 1H, J=7.7 Hz), 7.01 (d, 1H, J=7.7 Hz), 7.20(quint, 2H, J=8.1 Hz), 7.49 (m, 2H), 7.71 (d, 1H J=7.7 Hz), 7.88 (d, 1H,J=8.7 Hz), 8.33 (s, 1H), 8.42 (s, 1H), 13.11 (s, 1H). Anal.(C₃₀H₃₆N₄O₃Si.0.6 ethyl acetate) C, H, N.

(b) Example26—3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-6-(3-hydroxy-propyl)-2-methyl-phenol

By a procedure analogous to example 3, deprotection of 26a (99.4 mg,0.188 mmol) with tetrabutylammonium fluoride afforded 26 (26.9 mg, 36%)as a white solid: R_(f)=0.19 (70% ethyl acetate in hexanes); ¹H NMR(DMSO-d₆) δ1.74 (quint, 2H, J=7.4 Hz), 2.08 (s, 3H), 2.66 (t, 2H, J=7.4Hz), 3.47 (q, 2H, J=5.1 Hz), 4.59 (t, 1H, J=5.1 Hz), 6.74 (d, 1H, J=7.7Hz), 7.00 (d, 1H, J=7.7 Hz), 7.19 (quint, 2H, J=7.9 Hz), 7.38 (dd, 1HJ=8.5, 1.5 Hz), 7.50 (d, 1H, J=7.4 Hz), 7.67 (m, 2H), 8.30 (s, 1H), 8.37(s, 1H), 12.96 (s, 1H), 13.66 (s, 1H). Anal. (C₂₄H₂₂N₄O₂.0.4 ethylacetate) C, H, N.

EXAMPLE 27 1-[3-((E)-Styryl)-1H-indazol-5-yl]-piperidin-4-ol

(a) Intermediate 27a—4-(tert-Butyl-dimethyl-silanyloxy)-piperidine

Imidazole (4.18 g, 61.4 mmol), 4-hydroxypiperidine (2.07 g, 20.46 mmol),and tert-butyldimethylsilyl chloride (4.63 g, 30.7 mmol) were dissolvedin dichloromethane (50 mL) and stirred at 23° C. for 4 hours. Themixture was then washed with saturated aqueous sodium bicarbonatesolution (3×50 mL) and water (50 mL), dried over magnesium sulfate,filtered, and concentrated under high vacuum to give 27a (2.60 g, 59%)as a yellow oil which crystallizes on standing.: ¹H NMR (CDCl₃) δ0.05(s, 6H), 0.90 (s, 9H), 1.46 (m, 2H), 1.81 (m, 2H), 2.71 (m, 2H), 3.09(m, 3H), 3.77 (septet, 1H), J=3.9 Hz),. Anal. (C₁₁H₂₅NOSi.0.2 CH₂Cl₂) C,H, N.

(b) Intermediate27b—5-{4-[(Dimethyl-ethyl)-dimethyl-silanyloxy]-piperidin-1-yl}-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

Sodium tert-butoxide (163 mg, 1.70 mmol),tris(dibenzylidineacetone)-dipalladium(0) (26 mg,0.03 mmol), and CyMAP-1(See Old et. al., J. Am. Chem. Soc., 120, 9722 (1998)for the structureof this ligand) (33 mg, 0.085 mmol) were added to a degassed solution of27a (241.1 mg, 1.12 mmol) and iodide 7a′ (269.3 mg, 0.565 mmol), inethylene glycol dimethyl ether (DME, 2.0 mL). The mixture was heated inan 80° C. oilbath for 17 hours. After cooling to room temperature, themixture was diluted with ethyl acetate (50 mL) and filtered to removethe black precipitate. The filtrate was washed with water (10 mL) andsaturated aqueous sodium chloride (10 mL), dried over magnesium sulfate,filtered, concentrated, and purified by silica gel chromatography (10 to50% ethyl acetate in hexanes) to give 27b (177.7 mg, 56%) as an orangeoil: R_(f)=0.28 (20% ethyl acetate in hexanes); ¹H NMR (CDCl₃) δ−0.06(s, 9H), 0.09 (s, 6H), 0.90 (m, 2H), 0.92 (s, 9H), 1.80 (m, 2H), 1.97(m, 2H), 3.07 (m, 2H), 3.44 (m, 2H), 3.58 (t, 2H, J=8.4 Hz), 3.92 (m,1H), 5.69 (s, 2H), 7.29 (m, 2H), 7.41 (m, 6H), 7.61 (d, 2H, J=8.7 Hz).

(c) Example 27—1-[3-((E)-Styryl)-1H-indazol-5-yl]-piperidin-4-ol

By a procedure analogous to example 3, treatment of intermediate 27b(121.4 mg, 0.22 mmol) with tetrabutylammonium fluoride afforded 27 (33.1mg, 47%) as a yellow foam: R_(f)=0.15 (70% ethyl acetate/hexanes); ¹HNMR (DMSO-d₆) δ1.55 (m, 2H), 1.86 (m, 2H), 2.83 (m, 2H), 3.47 (m, 2H),3.61 (m, 1H), 4.68 (d, 1H, J=4.2 Hz), 7.22 (m, 2H), 7.37 (m, 5H), 7.55(d, 1H, J=16.5 Hz), 7.69 (d, 2H, J=7.2 Hz), 12.89 (s, 1H). Anal.(C₂₀H₂₁N₃O.0.4 H₂.0.4 ethyl acetate) C, H, N.

EXAMPLE 28 1-[3-((E)-Styryl)-1H-indazol-5-yl]-piperidin-3-ol

(a) Intermediate 28a—3-(tert-Butyl-dimethyl-silanyloxy)-piperidine

By a procedure analogous to the synthesis of 27a, 3-hydroxypiperidinehydrochloride (2.76 g, 20.06 mmol) was converted to 28a (2.92 g, 68%), ayellow oil which crystallizes on standing.: ¹H NMR (CDCl₃) δ0.05 (s,6H), 0.89 (s, 9H), 1.46 (m, 2H), 1.77 (m, 2H), 2.39 (br s, 1H), 2.61 (m,2H),2.82 (m, 1H), 2.97 (dd, 1H, J=12.3, 2.7 Hz), 3.66 (septet, 1H, J=3.6Hz). Anal. (C₁₁H₂₅NOSi.0.2 CH₂Cl₂) C, H, N.

Intermediate28b—5-{3-[(Dimethyl-ethyl)-dimethyl-silanyloxy]-piperidin-1-yl}-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1-H-indazole

28b was prepared by a procedure analogous to 27b synthesis.Intermediates 7a′ (269.3 mg, 0.565 mmol) and 28a (244 mg, 1.13 mmol)were used to form 28b (212.0 mg, 66%) as a brown oil: R_(f)=0.17 (10%ethyl acetate in hexanes); ¹H NMR (CDCl₃) δ−0.05 (s, 9H), 0.09 (s, 6H),0.92 (m, 2H), 0.96 (s, 9H), 1.44 (m, 1H), 1.65-2.05 (m, 3H), 2.69 (m,2H), 3.56 (m, 4H), 3.92 (m, 1H), 5.70 (s, 2H), 7.25 (m, 2H), 7.40 (m,6H), 7.60 (d, 2H, J=8.4 Hz). Anal. (C₃₂H₄₉N₃O₂Si₂.0.6 H₂O) C, H, N.

(c) Example 28—1-[3-((E)-Styryl)-1H-indazol-5-yl]-piperidin-3-ol

By a procedure analogous to example 3, treatment of intermediate 28b(181.5 mg, 0.322 mmol) with tetrabutylammonium fluoride afforded 28(47.6 mg, 46%) as a yellow foam: R_(f)=0.19 (70% ethyl acetate/hexanes);¹H NMR (DMSO-d₆) δ1.34 (m, 1H), 1.70 (m, 1H), 1.95 (m, 2H), 2.55 (m,1H), 2.72 (m 1H), 3.46 (m, 1H), 3.63 (m, 1H), 3.74 (m, 1H), 4.88 (d, 1H,J=4.5 Hz), 7.24 (dd, 1H, J=9.0, 1.8 Hz), 7.33 (t, 1H, J=7.2 Hz), 7.42(m, 5H), 7.63 (d, 1H, J=16.5 Hz), 7.76 (d, 2H, J=7.2 Hz), 12.97 (s, 1H).Anal. (C₂₀H₂₁N₃O.0.3 H₂O) C, H, N.

EXAMPLE 29[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-methanol

(a) Intermediate29a—{2-[5-(4,4,5,-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-yl}-methanol

By a procedure similar to the synthesis of boronic ester 19e, iodide 23c(512.8 mg, 0.985 mmol) was converted to boronic ester 29a (312.0 mg,61%), a white foam: R_(f)=0.28 (5% methanol in dichloromethane); ¹H NMR(DMSO-d₆) [Some peaks are doubled due to tautomeric isomerization]δ−0.13 (s, 9H), 0.83 (t, 2H, J=7.7 Hz), 1.35 (s, 12H), 3.60 (t, 2H,J=8.1 Hz), 4.87 (br s, 1H), 5.06 (br s, 1H), 5.24 (m, 1H), 5.90 (s, 2H),7.26 (m, 2H), 7.40 and 7.71 (2 d, 1H together, J=7.2 and 7.9 Hz), 7.82(m, 2H), 8.95 (s, 1H), 12.93 and 13.10 (2 s, 1H together). Anal.(C₂₇H₃₇BN₄O₄Si.0.5 H₂O) C, H, N.

(b) Intermediate29b—{2-[5-Isoquinolin-4-yl-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-yl}-methanol

By a procedure similar to the synthesis of 19f, 4-bromoisoquinoline (193mg, 0.927 mmol) was coupled with boronic ester 29a (241.2 mg, 0.463mmol) to give 29b (171.1 mg, 71%) as a white foam: R_(f)=0.22 (75% ethylacetate in hexanes); ¹H NMR (DMSO-d₆) [Some peaks are doubled due totautomeric isomerization] δ−0.08 (s, 9H), 0.88 (t, 2H, J=7.7 Hz), 3.68(t, 2H, J=7.9 Hz), 4.88 (d, 2H, J=5.3 Hz), 5.05 and 5.25 (2 br s, 1Htogether), 5.98 (s, 2H), 7.22 (m, 2H), 7.40 and 7.57 (2m, 1H together),7.77 (m, 4H), 8.07 (d, 1H, J=8.5 Hz), 8.27 (dd, 1H, J=7.21 1.5 Hz), 8.57(s, 1H), 8.70 (br s, 1H), 9.41 (s, 1H), 12.97 and 13.14 (2 s, 1Htogether). Anal. (C₃₀H₃₁N₅O₂Si.0.4 H₂O) C, H, N.

(c) Example29—[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-methanol

29 was prepared similar to example 3. Treatment of intermediate 29b(129.0 mg, 0.247 mmol) with tetrabutylammonium fluoride afforded 29(58.3 mg, 60%) as a white powder: ¹H NMR (DMSO-d₆) [Some peaks aredoubled due to tautomeric isomerization] δ4.88 (t, 2H, J=6.2 Hz), 5.03and 5.23 (2 t, 1H together, J=5.6 and 6.2 Hz), 7.20 (m, 2H), 7.38 and7.53 (m and d, 1H together, J=7.4 Hz for the doublet), 7.63 (dd, 1H,J=8.7, 1.3 Hz), 7.82 (m, 4H), 8.27 (d, 1H, J=7.4 Hz), 8.55 (s, 1H), 8.63and 8.66 (2 s, 1H together), 9.40 (s, 1H), 12.87 and 13.02 (2 s, 1Htogether), 13.81 and 13.86 (2 s, 1H together). Anal. (C₂₄H₁₇N₅O.0.4H₂O.0.3 CH₂Cl₂) C, H, N.

EXAMPLE 302-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-ethanol

(a) Intermediate30a—2-{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-yl}-ethanol

A suspension of 10% palladium on carbon (66 mg) and2-(2-amino-3-nitrophenyl)ethanol [See Seno, Kaoru; Hagishita, Sanji;Sato, Tomohiro; Kuriyama, Kaoru; J. Chem. Soc. Perkin Trans. 1; 2012(1984) for the synthesis of this reagent] (531.5 mg, 2.92 mmol) inabsolute ethanol (50 mL) was shaken under 40 psi hydrogen for 3 hours.After filtration and concentration, crude 2-(2,3-diaminophenyl)ethanol(474.4 mg) was obtained as a red oil, which crystallized on standing:R_(f)=0.08 (75% ethyl acetate in hexanes); ¹H NMR (DMSO-d₆) δ2.58 (t,2H, J=6.9 Hz), 3.53 (t, 2H, J=7.2 Hz), 4.32 (br s, 5H), 6.29 (m, 2H),6.40 (dd, 1H, J=6.9, 2.1 Hz).

Without further purification, this crude diamine was condensed withaldehyde 19f (1.10 g, 2.81 mmol) in the presence of sulfur, similar tothe synthesis of intermediate 7c′, affording 30a (930.8 mg, 63%) as ayellow foam: R_(f)=0.19 (ethyl acetate); ¹H NMR (DMSO-d₆) [Some peaksare doubled due to tautomeric isomerization] δ3.10 (m, 2H), 3.71 (s,3H), 3.74 (m, 2H), 4.66 and 4.80 (2 br s, 1H together), 5.82 (s, 2H),6.93 (d, 2H, J=8.7 Hz), 7.05 (m, 2H), 7.39 (m, 3H), 7.65 (d, 1H, J=9.2Hz), 7.81 (m, 3H), 8.00 (m, 1H), 8.26 (dd, 1H, J=7.2, 2.21 Hz), 8.54 (s,1H), 8.65 (s, 1H), 9.39 (s, 1H), 12.96 and 13.02 (2 s, 1H together).

(b) Example30—2-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-ethanol

Intermediate 30a (169.1 mg, 0.322 mmol) was deprotected by a syntheticmethod analogous to example 19, affording 30 (28.2 mg, 22%) as a whitepowder: R_(f)=0.33 (ethyl acetate); ¹H NMR (DMSO-d₆) [Some peaks aredoubled due to tautomeric isomerization] δ3.11 (m, 2H), 3.73 (m, 2H),4.68 and 4.85 (2 t, 1H together, J=5.2 and 5.5 Hz), 7.04 (m, 2H), 7.35and 7.47 (2 d, 1H together, J=7.9 and 7.2 Hz), 7.63 (d, 1H, J=8.7 Hz),7.83 (m, 4H), 8.26 (d, 1H, J=7.5), 8.5 (s, 1H), 8.63 (s, 1H), 9.39 (s,1H), 12.97 and 13.01 (2 s, 1H together), 13.86 and 13.87 (2 s, 1Htogether). Anal. (C₂₅H₁₉N₅O.0.3 H₂O.0.4 ethyl acetate.0.06 S) C, H, N.

EXAMPLE 31[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-dimethyl-amine

(a) Intermediate31a—{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-yl}-methanol

By a synthesis similar to the synthesis of 19h, aldehyde 19f (3.67 g,9.33 mmol) and diamine 23b (1.29 g, 9.33 mmol) were condensed in thepresence of sulfur to give 31a (2.60 g, 54%) as a yellow solid:R_(f)=0.19 (75% ethyl acetate in hexanes); ¹H NMR (DMSO-d₆) [Some peaksare doubled due to tautomeric isomerization] δ3.71 (s, 3H), 4.88 (d, 2H,J=5.5 Hz), 5.04 and 5.25 (2 t, 1H together, J=5.6 and 6.1 Hz), 5.81 and5.83 (2 s, 2H together), 6.93 (d, 2H, J=8.5 Hz), 7.21 (m, 2H), 7.38 and7.54 (2 d, 3H together, J=7.4 and 7.5 Hz), 7.66 (d, 1H, J=8.7 Hz), 7.77(m, 3H), 8.01 (dd, 1H, J=8.7, 4.0 Hz), 8.26 (d, 1H, J=7.7 Hz), 8.54 and8.55 (2 s, 1H together), 8.65 and 8.68 (2 s, 1H together), 9.39 (s, 1H),12.88 and 13.05 (2 s, 1H together). Anal. (C₃₂H₂₅N₅O₂.0.3 H₂O) C, H, N.

(b) Intermediate31b—{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-dimethyl-amine

Methane sulfonyl chloride (119.3 mg, 1.04 mmol) was added dropwise to asolution of 31a (527.5 mg, 1.03 mmol) and diisopropylethyl amine (153.3mg, 1.19 mmol) in tetrahydrofuran (12.0 mL), cooled to 0° C. in anicebath. After stirring at 0° C. for 2.5 hours, the reaction flask wasfitted with a dry ice-cooled cold finger condenser, and dimethyl aminegas was condensed into the reaction solution until the volume hadincreased by about 5 mL. Stirring was continued at 0° C. for 4 hours,then at room temperature for 15 hours. The mixture was partitionedbetween ethyl acetate (100 mL) and saturated aqueous sodium bicarbonatesolution (20 mL). The organic extracts were dried over magnesiumsulfate, filtered, concentrated, and columned (silica gel, 5 to 10%methanol in dichloromethane), affording 31b (250.2 mg, 45%) as a paleyellow solid: R_(f)=0.26 (10% methanol in dichloromethane); ¹H NMR(DMSO-d₆) δ2.20 (s, 6H), 3.71 (s, 3H), 3.84 (s, 2H), 5.83 (s, 2H), 6.93(d, 2H, J=8.7 Hz), 7.14 (m, 2H), 7.36 (d, 2H, J=8.5 Hz), 7.48 (m, 1H),7.67 (d, 1H, J=8.9 Hz), 7.77 (quintet, 2H, J=6.4 Hz), 7.89 (m, 1H), 8.00(d, 1H, J=8.9 Hz), 8.26 (d, 1H, J=7.5 Hz), 8.55 Hz), 8.55 (s, 1H), 8.71(s, 1H), 9.39 (s, 1H), 13.03 (br s, 1H). Anal. (C₃₄H₃₀N₆O.1.1 H₂O) C, H,N.

Example31—[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-dimethyl-amine

A mixture of 31b (125.7 mg, 0.233 mmol), anisole (252 mg, 2.33 mmol),trifluoroacetic acid (2.3 mL), and concentrated sulfuric acid (0.2 mL)was stirred at room temperature for 66 hours, then added dropwise to arapidly stirred mixture of saturated aqueous sodium bicarbonate (75 mL)and ethyl acetate (25 mL). The layers were separated and the aqueouslayer extracted with ethyl acetate (2×50 mL). The combined organiclayers were dried over magnesium sulfate, filtered, concentrated, andpurified by silica gel chromatography (25 to 40% methanol indichloromethane) to give 31 (35.8 mg, 37%) as a white powder: R_(f)=0.09(10% methanol in dichloromethane); ¹H NMR (DMSO-d₆) [Some peaks aredoubled due to tautomeric isomerization]δ2.15 and 2.21 (2 br s, 6Htogether), 3.80 (s, 2H), 7.12 (br s, 2H), 7.40 and 7.54 (2 m, 1Htogether), 7.64 (d, 1H, J=9.0 Hz), 7.83 (m, 4H), 8.26 (d, 1H, J=7.5 Hz),8.55 (s, 1H), 8.63 and 8.73 (2 br s, 1H together), 9.39 (s, 1H), 13.02(br s, 1H), 13.83 (br s, 1H). Anal. (C₂₆H₂₂N₆.0.7 H₂O.1.0CH₃OH) C, H, N.

EXAMPLE 32[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-methyl-amine

(a) Intermediate32a—{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1benzoimidazol-4-ylmethyl}-methyl-amine

By a procedure similar to the synthesis of 31b, alcohol 31a (516.6 mg,1.01 mmol) was treated with methanesulfonyl chloride anddiisopropylethyl amine at 0° C. for 1 hour. Instead of condensed gas,however, a solution of methylamine in tetrahydrofuran (2.0 M, 5.0 mL)was then added, and stirring continued at room temperature for 15 hours.Extractive workup and silica gel chromatography similar to 31b affordedmono-methyl analog 32a (170.5 mg, 32%) as an off-white solid: R_(f)=0.16(1:20:300 concentrated aqueous NH₄OH:ethanol:dichloromethane); ¹H NMR(DMSO-d₆) δ2.26 (s, 3H), 3.71 (s, 3H), 4.03 (s, 2H), 5.82 (s, 2H), 6.93(d, 2H, J=8.7 Hz), 7.14 (d, 2H, J=4.7 Hz), 7.37 (d, 2H, J=8.7 Hz), 7.46(m, 1H), 7.67 (dd, 1H, J=8.7, 1.3 Hz), 7.77 (m, 2H), 7.89 (d, 1H, J=7.7Hz), 8.01 (d, 1H, J=8.5 Hz), 8.25 (dd, 1H, J=7.0, 1.8 Hz), 8.55 (s, 1H),8.68 (s, 1H), 9.39 (s, 1H). Anal. (C₃₃H₂₈N₆O.0.6 H₂O) C, H, N.

(b) Example32—[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-methyl-amine

Deprotection by a procedure similar to the synthesis of 31 afforded 32(47.5 mg, 63%) as an off-white foam: R_(f)=0.29 (1:20:100 concentratedaqueous NH₄OH:ethanol:dichloromethane); ¹H NMR (DMSO-d₆) δ2.30 (s, 3H),4.07 (s, 2H), 7.15 (d, 2H, J=4.5 Hz), 7.47 (m, 1H), 7.64 (dd, 1H, J=8.5,1.5 Hz), 7.83 (m, 4H), 8.26 (d, 1H, J=7.2 Hz), 8.56 (s, 1H), 8.66 (s,1H), 9.39 (s, 1H). Anal. (C₂₅H₂₀N₆.1.0EtOH.0.2 hexanes) C, H, N.

EXAMPLE 334-[3(4Pyrrolidin-1-ylmethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

(a) Intermediate33a—4-[1-(4-Methoxy-benzyl)-3-(4-pyrrolidin-1-ylmethyl-1H-benzoimidazol-2-yl)1H-indazol-5-yl]-isoquinoline

By a synthetic method analogous to the synthesis of 31 b, alcohol 31 a(435.0 mg, 0.850 mmol) was treated with methanesulfonyl chloride anddiisopropylethyl amine at 0° C. for 2 hours. Pyrrolidine (605 mg, 8.5mmol) was added, and the mixture allowed to warm to room temperatureover 20 hours. Extractive workup and silica gel chromatography similarto 31b afforded 33a (303.0 mg, 63%) as a yellow foam: R_(f)=0.13(1:20:400 concentrated aqueous. NH₄OH:ethanol:dichloromethane); ¹H NMR(DMSO-d₆) δ1.61 (br s, 4H), 2.51 (br s, 4H), 3.71 (s, 3H), 3.97 (s, 2H),5.83 (s, 2H), 6.93 (d, 2H, J=8.8 Hz), 7.14 (d, 2H, J=3.6 Hz), 7.36 (d,2H, J=8.7 Hz), 7.45 (m, 1H), 7.67 (d, 1H, J=8.5 Hz), 7.76 (m, 2H), 7.89(m, 1H), 8.00 (d, 1H, J=8.7 Hz), 8.25 (d, 1H, J=6.6 Hz), 8.54 (s, 1H),8.70 (br s, 1H), 9.39 (s, 1H), 13.03 (br s, 1H). Anal. (C₃₆H₃₂N₆O.0.2CH₂Cl₂) C, H, N.

(b) Example33—4-[3-(4-Pyrrolidin-1-ylmethyl-1H-benzoimidazol-2-yl)1H-indazol-5-yl]-isoquinoline

A solution of 33a (109.2 mg, 0.193 mmol) in 25% concentrated sulfuricacid/trifluoroacetic acid (2.0 mL) was stirred at room temperature for21 hours, then added dropwise to a rapidly stirred mixture oftetrahydrofuran (25 mL), and saturated aqueous sodium carbonate (25 mL).Ethyl acetate (25 mL) and water (15 mL) were added, and the layersseparated. The aqueous layer was extracted with ethyl acetate (3×50 mL),and the combined organic fractions dried over magnesium sulfate,filtered and concentrated. Purification by silica gel chromatography(1:20:100 concentrated aqueous NH₄OH:ethanol:dichloromethane) afforded33 (25.4 mg, 30%) as a white powder: ¹H NMR (CD₃OD) δ1.77 (br s, 4H),2.69 (br s, 4H), 4.12 (s, 2H), 7.24 (d, 2H, J=4.0 Hz), 7.80 (m, 5H),8.06 (d, 1H, J=7.9 Hz), 8.23 (d, 1H, J=7.5 Hz), 8.53 (s, 1H), 8.69 (s,1H), 9.29 (s, 1H). Anal. (C₂₈H₂₄N₆.0.9 MeOH) C, H, N.

EXAMPLE 344-{3-[4-(2-Pyrrolidin-1-ylethyl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-isoquinoline

(a) Intermediate34a—4-{-(4-Methoxy-benzyl)-3-[4-(2-pyrrolidin-1-yl-ethyl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-isoquinoline

By a procedure similar to the synthesis of 33a, alcohol 30a (441.5 mg,0.84 mmol) was converted into 34a (204.6 mg, 42%), an off-white foam:R_(f)=0.08 (1:20:400 concentrated aqueousNH₄OH:ethanol:dichloromethane); ¹H NMR (DMSO-d₆) δ1.38 (br s, 4H), 2.31(br s, 4H), 2.79 (m, 2H), 3.07 (m, 2H), 3.71 (s, 3H), 5.81 (s, 2H), 6.93(d, 2H, J=8.8Hz), 6.98 (d, 1H, J=7.2 Hz), 7.08 (t, 1H, J=7.7 Hz, 7.36(d, 2H, J=8.7 Hz), 7.39 (m, 1H), 7.66 (dd, 1H, J=8.5, 1.5 Hz), 7.76 (m,2H), 7.89 (d, 1H, J=7.7 Hz), 8.01 (d, 1H, J=8.7 Hz), 8.25 (d, 1H, J=7.4Hz), 8.53 (s, 8.53 (s, 1H), 8.75 (br s, 1H), 9.38 (s, 1H), 13.00 (br s,1H). Anal. (C₃₇H₃₄N₆O.0.6 H₂O) C, H, N.

(b) Example34—4-{3-[4-(2-Pyrrolidin-1-yl-ethyl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-isoquinoline

34 was prepared similar to example 33. Treatment of 34a (66.2 mg, 0.114mmol) with 3:1 trifluoroacetic acid/sulfuric acid yielded 34 (24.7 mg,47%) as a white powder: R_(f)=0.38 (1:20:100 concentrated aqueousNH₄OH:ethanol:dichloromethane); ¹H NMR (DMSO-d₆) δ1.37 (br m, 6H), 2.27(br m, 2H), 2.80 (m, 2H), 3.07 (m, 2H), 6.98 (d, 1H, J=7.2 Hz), 7.09 (t,1H, J=7.5 Hz), 7.36 (br s, 1H), 7.63 (dd, 1H, J=8.5, 1.5 Hz), 7.82 (m,4H), 8.26 (d, 1H, J=7.4 Hz), 8.54 (s, 1H), 8.75 (br s, 1H), 9.39 (s,1H), 12.98 (br s, 1H), 13.79 (s, 1H). Anal. (C₂₉H₂₆N₆.0.7 EtOH) C, H, N.

EXAMPLE 353-{[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-amino}-2-methyl-propan-1-ol

(a) Intermediate35a—Cyclopropylmethyl-{2-[5-isoquinolin-4-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-amine

By a procedure similar to 31b synthesis, alcohol 31a (512.0 mg, 1.00mmol) was treated with methanesulfonyl chloride and diisopropylethylamine at 0° C. for 1 hour. Aminomethylcyclopropane (712 mg, 10.0 mmol)was then added, and stirring continued at room temperature for 15 hours.After extractive workup and column chromatography similar to 31 b,intermediate 35a (209.3 mg, 37%) was obtained as an off-white powder:R_(f)=0.16 (1:20:300 concentrated aqueousNH₄OH:ethanol:dichloromethane); ¹H NMR (DMSO-d₆) δ−0.24 (br s, 2H),−0.04 (br s, 2H), 0.66 (br s, 1H), 2.30 (br s, 2H), 3.71 (s, 3H), 4.04(br s, 2H), 5.83 (s, 2H), 6.93 (d, 2H, J=8.7 Hz), 7.11 (m, 2H), 7.37 (d,2H, J=8.7 Hz), 7.42 (m, 1H), 7.67 (dd, 1H, J=8.7, 1.5 Hz), 7.76 (m, 2H),7.87 (d, 1H, J=8.1 Hz), 8.02 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H, J=6.8, 1.9Hz), 8.53 (s, 1H), 8.68 (br s, 1H), 9.38 (s, 1H). Anal.(C₃₆H₃₂N₆O.0.5H₂O) C, H, N.

(b) Example35—3-{[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-amino}-2-methyl-propan-1-ol

35 was prepared similar to example 33. Treatment of 35a (107.1 mg, 0.19mmol) with 3:1 trifluoroacetic acid/sulfuric acid yielded ring-openedanalog 35 (25.3 mg, 29%) as a white powder: R_(f)=0.35 (1:20:100concentrated aqueous NH₄OH:ethanol: dichloromethane); ¹H NMR (CD₃OD)δ0.67 (d, 3H, J=6.8 Hz), 1.33 (m, 1H), 1.80 (m, 1H), 2.60 (m, 1H), 2.75(m, 1H), 3.20 (m, 1H), 4.26 (s, 2H), 7.22 (m, 2H), 7.57 (d, 1H, J=7.7Hz), 7.63 (dd, 1H, J=8.7, 1.7 Hz), 7.79 (m, 3H), 7.99 (d, 1H, J=7.5 Hz),8.22 (d, 1H, J=7.5 Hz), 8.51 (s, 1H), 8.72 (br s, 1H), 9.29 (s, 1H). ¹³CNMR (CD₃OD, DEPT) δ15.0 (CH₃), 35.6 (CH), 50.9 (CH₂), 54.0 (CH₂), 67.4(CH₂), 111.7 (CH), 123.4 (CH), 124.0 (CH), 124.3 (CH), 125.8 (CH), 128.9(CH), 129.3 (CH), 130.4 (CH), 132.6 (CH), 142.9 (CH), 152.6 (CH). Anal.(C₂₈H₂₆N₆O. 0.6 CH₂Cl₂.0.4hexanes) C, H, N.

EXAMPLE 36Diethyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-amine

(a) Intermediate36a—Diethyl-{2-[5-isoquinolin4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-amine

By a procedure similar to 31b, alcohol 31a (511.4 mg, 1.00 mmol) wastreated with methanesulfonyl chloride and diisopropylethyl amine at 0°C. for 2.5 hours. Diethylamine (731.4 mg, 10.0 mmol) was then added, andstirring continued at room temperature for 25 hours. After extractiveworkup and column chromatography similar to 31b, intermediate 36a (434.6mg, 77%) was obtained as a yellow foam: R_(f)=0.22 (1:20:400concentrated aqueous NH₄OH:ethanol:dichloromethane); ¹H NMR (DMSO-d₆)[Some peaks are doubled due to tautomeric isomerization]δ0.87 and 1.01(2br s, 6H together), 2.41 and 2.56 (2 br s, 4H together), 3.71 (s, 3H),3.89 and 3.94 (2 br s, 2H together), 5.82 (s, 2H), 6.92 (d, 2H, J=8.7Hz), 7.13 (m, 2H), 7.37 (d, 2H, J=8.5 Hz), 7.50 (m, 1H), 7.67 (d, 1H,J=8.7 Hz), 7.76 (m, 2H), 7.91 (m, 1H), 8.01 (d, 1H, J=8.7 Hz), 8.25 (dd,1H, J=6.6, 1.9 Hz), 8.53 (s, 1H), 8.63 and 8.77 (2 br s, 1H together),9.38 (s, 1H), 13.02 (s, 1H). Anal. (C₃₆H₃₄N₆O.0.4 H₂O) C, H, N.

(b) Example36—Diethyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-amine

Similar to example 33, treatment of 36a (266.5 mg, 0.47 mmol) with 3:1trifluoroacetic acid/sulfuric acid yielded 36 (67.5 mg, 32%) as a whitepowder: R_(f)=0.30 (1:20:200 concentrated aqueousNH₄OH:ethanol:dichloromethane); ¹H NMR (DMSO-d₆) [Some peaks are doubleddue to tautomeric isomerization]δ0.94 (br m, 6H), 2.44 and 2.55 (2 br s,4H together), 3.94 (br s, 2H), 7.14 (br s, 2H), 7.39 and 7.50 (2 br s,1H together), 7.64 (dd, 1H, J=8.7, 1.5 Hz), 7.77 (m, 4H), 8.25 (d, 1H,J=7.4 Hz), 8.54 (s, 1H), 8.63 and 8.74 (2 br s, 1H together), 9.39 (s,1H), 12.99 (s, 1H) 13.81 (s, 1H). Anal. (C₂₈H₂₆N₆.0.5 EtOH) C, H, N.

EXAMPLE 37Ethyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-amine

(a) Intermediate37a—Ethyl-{2-[5-isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-amine

By a synthetic method similar to 31b, alcohol 31a (371.5 mg, 0.726 mmol)was treated with methanesulfonyl chloride and diisopropylethyl amine at0° C. for 2.5 hours. The reaction flask was then fitted with a dryice-cooled cold finger condenser, and ethylamine gas was condensed intothe reaction solution until the volume had increased by about 5 mL.Stirring was continued at room temperature for 15 hours. Afterextractive workup and column chromatography similar to 31 b,intermediate 37a (260.1 mg, 67%) was obtained as a pale yellow foam: ¹HNMR (DMSO-d₆) δ0.84 (br s, 3H), 3.39 (br s, 2H), 3.71 (s, 3H), 4.04 (s,2H), 5.82 (s, 2H), 6.93 (d, 2Hz), 7.12 (m, 2H), 7.37 (d, 2H, J=8.7 Hz),7.44 (m, 1H), 7.67 (dd, 1H, J=8.7, 1,5 Hz), 7.76 (m, 2H), 7.89 (m, 1H),8.01 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H, J=6.6, 1.9 Hz), 8.54 (s, 1H), 8.67(s, 1H), 9.39 (s, 1H). Anal. (C₃₄H₃₀N₆O.0.7 H₂O) C, H, N.

(b) Example37—Ethyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-amine

Similar to example 33, treatment of 37a (123.3 mg, 0.229 mmol) with 3:1trifluoroacetic acid/sulfuric acid yielded 37 (21.8 mg, 23%) as anoff-white powder: ¹H NMR (DMSO-d₆) 8 0.84 (br s, 3H), 2.57 (br s, 2H),4.10 (s, 2H), 7.13 (m, 2H), 7.46 (m, 1H), 7.64 (dd, 1H, J=8.7, 1.7 Hz),7.80 (m, 4H), 8.26 (dd, 1H, J=7.2, 1.7 Hz), (s, 1H), 8.66 (s, 1H), 9.39(s, 1H), 13.85 (br s, 1H). Anal. (C₂₆H₂₂N₆.0.6 EtOH.1.0CH₂Cl₂) C, H, N.

EXAMPLE 38Isopropyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-amine

(a) Intermediate38a—Isopropyl-{2-[5-isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-amine

By a procedure similar to 31 b, alcohol 31a (518.0 mg, 1.01 mmol) wastreated with methanesulfonyl chloride and diisopropylethyl amine at 0°C. for 2.5 hours. Isopropyl amine (597 mg, 10.1 mmol) was then added,and stirring continued at room temperature for 24 hours. Afterextractive workup and column chromatography similar to 31b, intermediate38a (417.8 mg, 75%) was obtained as a yellow foam: ¹H NMR (DMSO-d₆)δ0.77 (br s, 6H), 2.63 (br s, 1H), 3.71 (s, 3H), 4.02 (br s, 2H), 5.82(s, 2H), 6.93 (d, 2H, J=8.7 Hz), 7.11 (m, 2H), 7.37 (d, 2H, J=8.7 Hz),7.42 (m, 1H), 7.67 (dd, 1H, J=8.7, 1.5 Hz), 7.76 (m, 2H), 7.88 (d, 1H,J=7.7 Hz), 8.02 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H, J=6.6, 2.1 Hz), 8.53(s, 1H), 8.69 (br s, 1H), 9.38 (s, 1H). Anal. (C₃₅H₃₂N₆O.0.7 H₂O) C, H,N.

(b) Example38—Isopropyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzo-imidazol-4-ylmethyl]-amine

38 was prepared similar to example 33. Treatment of 38a (243.3 mg, 0.44mmol) with 3:1 trifluoroacetic acid/sulfuric acid yielded 38 (89.9 mg,47%) as an off-white powder: ¹H NMR (CD₃OD) δ1.03 (d, 6H, J=6.4 Hz),2.99 (septet, 1H, J=6.4 Hz), 4.27 (s, 2H), 7.23 (m, 2H), 7.57 (dd, 1H,J=7.7, 1.1 Hz), 7.67 (dd, 1H, J=8.7, 1.7 Hz), 7.81 (m, 3H), 8.01 (d, 1H,J=8.3 Hz), 8.23 (d, 1H, J=7.5 Hz), 8.51 (s, 1H), 8.71 (br s, 1H), 9.30(s, 1H).

EXAMPLE 39tert-Butyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-amine

(a) Intermediate39a—tert-Butyl-{2-[5-isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-amine

By an analogous method to 31b, alcohol 31a (623.2 mg, 1.22 mmol) wastreated with methanesulfonyl chloride and diisopropylethyl amine at 0°C. for 1 hour. tert-Butylamine (890 mg, 12.2 mmol) was then added, andstirring continued at room temperature for 20 hours. After extractiveworkup and column chromatography similar to 31b, intermediate 39a (299.7mg, 43%) was obtained as a yellow foam: ¹H NMR (CD₃OD) δ1.01 (s, 9H),3.76 (s, 3H), 4.11 (s, 2H), 5.78 (s, 2H), 6.91 (d, 2H, J=8.7 Hz), 7.19(m, 2H), 7.36 (d, 2H, J=8.7 Hz), 7.50 (dd, 1H, J=7.9, 1.1 Hz), 7.62 (dd,1H, J=8.7, 1.7 Hz), 7.77 (m, 3H), 7.95 (d, 1H, J=7.9 Hz), 8.22 (dd, 1H,J=7.0, 1.7 Hz), 8.48 (s, 1H), 8.74 (s, 1H), 9.29 (s, 1H). Anal.(C₃₆H₃₄N₆O.0.3 H₂O) C, H, N.

(b) Example39—tert-Butyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzo-imidazol-4-ylmethyl]-amine

A solution of 39b (103.7 mg, 0.183 mmol), trifluoromethanesulfonic acid(0.48 mL), and trifluoroacetic acid (1.6 mL) was stirred at roomtemperature for 17 hours, and then at 100° C. for 1.5 hours. Thesolution was added dropwise to a rapidly stirred mixture of concentratedaqueous NH₄OH (10 mL), water (10 mL), and ethyl acetate (10 mL).Extraction and purification similar to example 33, afforded 39 (40.2 mg,49%) as a white powder: ¹H NMR (CD₃OD) δ1.30 (s, 9H), 4.56 (s, 2H), 7.33(m, 2H), 7.68 (m, 2H), 7.81 (m, 3H), 8.01 (d, 1H, J=8.5 Hz), 8.25 (d,1H, J=8.5 Hz), 8.51 (s, 1H), 8.73 (s, 1H), 9.32 (s, 1H). Anal.(C₂₈H₂₆N₆.1.6 HOAc) C, H, N.

EXAMPLE 404-[3-(4-Imidazol-1-ylmethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

(a) Intermediate40a—4-[3(4-Imidazol-1-ylmethyl-1H-benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-isoquinoline

By an analogous method to 31b, alcohol 31a (572.0 mg, 1.12 mmol) wastreated with methanesulfonyl chloride and diisopropylethyl amine at 0°C. for 1 hour. Imidazole (761 mg, 11.2 mmol) was then added, andstirring was continued at room temperature for 24 hours. Afterextractive workup and column chromatography similar to 31b, intermediate40a (269.1 mg, 43%) was obtained as a white powder: ¹H NMR (CD₃OD) δ3.77(s, 3H), 5.58 (s, 2H), 5.79 (s, 2H), 6.73 (br s, 1H), 6.91 (d, 2H, J=8.8Hz), 7.07 (d, 1H, J=7.4 Hz), 7.23 (m, 2H), 7.36 (d, 2H, J=8.8 Hz),7.53-7.83 (m, 6H), 8.03 (d, 1H, J=7.9 Hz), 8.22 (d, 1H, J=7.9 Hz), 8.51(s, 1H), 8.73 (br s, 1H), 9.28 (s, 1H). Anal. (C₃₅H₂₇N₇O) C, H, N.

(b) Example40—4-[3-(4-Imidazol-1-ylmethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

A solution of 40a (152.0 mg, 0.271 mmol), trifluoromethanesulfonic acid(0.271 mL), and trifluoroacetic acid (2.71 mL) was stirred at 60° C. for1 hour. The solution was added dropwise to a rapidly stirred mixture ofconcentrated aqueous NH₄OH (10 mL), water (10 mL), THF (10 mL), andethyl acetate (20 mL). Extraction and purification similar to example33, afforded crude 40 as a pink solid (24.9 mg), which still showedimpurities in the ¹H NMR spectrum. Trituration from acetonitrileafforded pure 40 (11.0 mg, 9%) as a pink powder: ¹H NMR (CD₃OD) δ5.59(s, 2H), 6.74 (br s, 1H), 7.08 (d, 1H, J=7.4 Hz), 7.25 (m, 2H),7.55-7.85 (m, 6H), 8.07 (d, 1H, J=7.9 Hz), 8.24 (d, 1H, J=7.5 Hz), 8.54(s, 1H), 8.72 (br s, 1H), 9.30 (s, 1H). HRMS calculated for C₂₇H₂₀N₇442.1780 (MH⁺), found 442.1794.

EXAMPLE 41 5-(3-Methyl-pyridin-4-yl)-3-(E)-styryl-1H-indazole

(a) Intermediate41a—5-(3-Methyl-pyridin-4-yl)-3-(E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

Intermediate 16a (300 mg, 0.63 mmol), 4-bromo-3-methyl-pyridine (seeBaliki et al., Gazz. Chim. Ital. 124, 9, 1994, 385-386) (112 mg, 0.65mmol), and sodium carbonate (140 mg, 1.3 mmol) were stirred in DME (6mL)/ H₂O (1 mL) in a flask purged with argon.Tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) was added,and the reaction stirred at reflux under argon for 24 hours. Thesolution was diluted with ethyl acetate, washed with H₂O and brine,dried over Na₂SO₄, and concentrated in vacuo. Purification by silica gelchromatography (20% ethyl acetate/hexanes) gave 234 mg (84%) ofintermediate 41a as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ8.56 (s, 1H),8.52 (d, 1H, J=7.8 Hz), 7.95 (s, 1H), 7.24-7.67 (m, 10H), 5.78 (s, 2H),3.64 (t, 2H, J=8.1 Hz), 2.33 (s, 3H), 0.94 (t, 2H, J=8.1 Hz), −0.04 (s,9H). Anal. (C₂₇H₃₀N₃OSi. 0.2 H₂O) C, H, N.

(b) Example 41—5-(3-Methyl-pyridinyl)3-(E)-styryl-1H-indazole

Intermediate 41a (218 mg, 0.49 mmol) was stirred in a mixture ofethylenediamine (0.34 mL, 4.9 mmol) and TBAF (1 M in THF, 2.5 mL, 2.5mmol) at 72° C. for 20 hours. The solution was diluted with ethylacetate, washed with sat. NaHCO₃ and brine, dried (Na₂SO₄), andconcentrated in vacuo. Purification by silica gel chromatography (1:1:1ethyl acetate/THF/hexanes) gave 122 mg (79%) of the title compound as awhite solid. ¹H NMR (300 MHz, DMSO-d₆) δ13.29 (s, 1H), 8.52 (s, 1H),8.46 (d, 1H, J=4.8 Hz), 8.22 (s, 1H), 7.55-7.73 (m, 5H), 7.26-7.44 (m,5H), 2.31 (s, 3H). Anal. (C₂₁H₁₇N₃) C, H, N. MS (ES) [m+H]/z calculated312, found 312; [m−H]/z calculated 310, found 310.

EXAMPLE 42 5-(4-Chloro-pyridin-3-yl)-3-(E)-styryl-1H-indazole

(a) Intermediate42a—5-(4Chloro-pyridin-3-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

The title compound was prepared in 73% yield from intermediate 16a and4-chloro-3-iodo-pyridine (see Cho et al., Heterocycles, 43, 8, 1996,1641-1652) analogous to intermediate 41a. ¹H NMR (300 MHz, CDCl₃) δ8.67(s, 1H), 8.52 (d, 1H, J=7.8 Hz), 8.08 (s, 1H), 7.26-7.70 (m, 10H), 5.79(s, 2H), 3.64 (t, 2H 0.94 (t, 2H, J=8.1 Hz), −0.03 (s, 9H). Anal.(C₂₆H₂₈CIN₃OSi. 0.3 H₂O)

(b) Example 42—5-(4-Chloro-pyridin-3-yl)-3-(E)-styryl-1H-indazole

The title compound was prepared in 66% yield by the SEM-deprotection ofintermediate 42a in a method analogous to example 41. ¹H NMR (300 MHz,DMSO-d₆) δ13.30 (s, 1H), 8.70 (s, 1H), 8.56 (d, 1H, J=5.4 Hz), 8.31 (s,1H), 7.63-7.73 (m, 4H), 7.57 (d, 2H, J=4.2 Hz), 7.50 (dd, 1H, J=8.4, 1.2Hz), 7.26-7.40 (m, 3H) (C₂₀H₁₄CIN₃. 0.05 H₂O) C, H, N. MS (ES) [m+H]/zcalculated 332/334, found 332/334; [m−H]/z calculated 330/332, found330/332.

EXAMPLE43 5-(4-Methyl-pyridin-3-yl)-3-(E)-styryl-1H-indazole

(a) Intermediate43a—5-(4-Methyl-pyridin-3-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

The title compound was prepared in 90% yield from intermediate 16a and3-bromo-4-methyl-pyridine similar to the procedure for intermediate 41a.¹H NMR (300 MHz, CDCl₃) δ8.54 (s, 1H), 8.50 (d, 1H, J=7.8 Hz), 7.95 (s,1H), 7.23-7.67 (m, 10), 5.78 (s, 2H), 3.64 (t, 2H, J=8.1 Hz), 2.33 (s,3H), 0.94 (t, 2H, J=8.1 Hz), −0.04 (s, 9H). Anal. (C₂₇H₃₁N₃OSi) C, H, N.

(b) Example 43—5-(4-Methyl-pyridin-3-yl)-3-(E)-styryl-1H-indazole

The title compound was prepared in 48% yield by the SEM-deprotection ofintermediate 43a in a method analogous to example 41. ¹H NMR (300 MHz,DMSO-d₆) δ13.26 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H, J=4.8 Hz), 8.20 (s,1H), 7.71 (d, 2H, J=7.2 Hz), 7.55-7.64 (m, 3H), 7.26-7.42 (m, 5H), 2.31(s, 3H). Anal. (C₂₁H₁₇N₃. 0.13 H₂O) C, H, N. MS (ES) [m+H]/z calculated312, found 312; [m−H]/z calculated 310 found 310.

EXAMPLE 44 5-Fluoro-4-[3-((E)-styryl)-1H-indazol-5-yl]-isoquinoline

(a) Intermediate 44a—4-Bromo-5-fluoro-isoquinoline

5-Amino-4-bromo-isoquinoline (see Gordon et al., J. Heterocycl. Chem.,4, 1967, 410-411) (1.86 g, 8.34 mmol) was stirred in 48% fluoroboricacid (15 mL)/EtOH (15 mL) until completely dissolved. The solution wascooled to 0° C., and sodium nitrite (660 mg, 9.59 mmol) in H₂O (1 mL)was added dropwise. The solution was diluted with Et₂O (30 mL), and thetan diazonium fluoroborate salt was collected by filtration and driedunder vacuum. The solid was placed in a flask and carefully heated overa flame to expel nitrogen. The dark brown residue was diluted with 10%NaOH and extracted with chloroform. Organics were washed with brine,dried over MgSO₄, and concentrated in vacuo. Purification by silica gelchromatography (40% to 50% ethyl acetate/hexanes) gave 798 mg (42%) of4-bromo-5-fluoro-isoquinoline as a white solid. ¹H NMR (300 MHz, CDCl₃)δ9.36 (d, 1H, J=2.4 Hz), 8.74 (s, 1H), 8.07-8.11 (m, 1H), 7.70-7.80 (m,2H). Anal. (C₉H₅BrFN) C, H, N.

(b) Intermediate44b—5-Fluoro-4-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-isoquinoline

The title compound was prepared in 83% yield from intermediate 16a and4-bromo-5-fluoro-isoquinoline similar to intermediate 41a. ¹H NMR (300MHz, CDCl₃) δ9.32 (d, 1H, J=1.8 Hz), 8.52 (s, 1H), 8.07 (s, 1H), 7.91(dd, 1H, J=8.1, 0.9 Hz), 7.26-7.66 (m, 11H), 5.80 (s, 2H), 3.67 (t, 2H,J=8.1 Hz), 0.95 (t, 2H, J=8.1 Hz), −0.03 (s, 9H). Anal. (C₃₀H₃₀FN₃OSi.0.2 H₂O) C, H, N.

(c) Example 44—5-Fluoro-4-[3-((E)-styryl)-1H-indazol-5-yl]-isoquinoline

The title compound was prepared in 83% yield by the SEM-deprotection ofintermediate 44b in a manner analogous to example 41. ¹H NMR (300 MHz,DMSO-d₆) δ13.26 (s, 1H), 9.44 (d, 1H, J=1.8 Hz), 8.47 (s, 1H), 8.29 (s,1H), 8.12 (d, 1H, J=7.2 Hz), 7.44-7.78 (m, 8H), 7.35 (t, 2H, J=7.2 Hz),7.24 (t, 1H, J=7.2 Hz). Anal. (C₂₄H₁₆FN₃.0.6 H₂O) C, H, N. MS (ES)[m+H]/z calculated 366, found 366; [m−H]/z calculated 364, found 364.

EXAMPLE 45 4-[3-((E)-Styryl)-1H-Indazol-5-yl-isoquinolin-8-ylamine

(a) Intermediate45a—4-[3-((E)-Styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-isoquinolin-8-ylamine

The title compound was prepared in 82% yield from intermediate 16a and8-amino-4-bromo-isoquinoline (see Elpern et al., J. Amer. Chem. Soc.,68, 1946, 1436) similar to the procedure for intermediate 41a. ¹H NMR(300 MHz, CDCl₃) δ9.36 (d, 1H, J=0.6 Hz), 8.53 (s, 1H), 8.13 (s, 1H)7.26-7.72 (m, 11H), 6.86 (dd, 1H, J=7.5, 0.6 Hz), 5.81 (s, 2H), 4.51 (s,2H), 3.66 (t, 2H, J=8.1 Hz), 0.96 (t, 2H, J=8.1 Hz), −0.03 (s, 9H).Anal. (C₃₀H₃₂N₄OSi) C, H, N.

(b) Example 45-4-[3-((E)-Styryl)-1H-indazol-5-yl]-isoquinolin-8-ylamine

The title compound was prepared in 70% yield by the SEM-deprotection ofintermediate 45a in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.30 (s, 1H), 9.50 (s, 1H), 8.36 (s, 1H),8.26 (s, 1H), 7.24-7.71 (m, 10H), 6.91 (d, 1H, J=7.8 Hz), 6.77 (t, 1H,J=7.8 Hz), 6.33 (s, 2H). Anal. (C₂₄H₁₈N₄.0.45 H₂O) C, H, N. MS (ES)[m+H]/z calculated 363, found 363.

EXAMPLE 46 5-(4-Chloro-5-ethyl-pyridin-3-yl)-3-(E)-styryl-1H-indazole

(a) Intermediate 46a—4-Chloro-3-ethyl-5-iodo-pyridine

LDA was prepared by the addition of n-butyllithium (2.5 M in hexanes,0.95 mL, 2.38 mmol) to a solution of diisopropylamine (0.345 mL, 2.42mmol) in THF (5 mL) at −20° C. After 10 minutes, the solution was cooledto −78° C. 4-Chloro-3-iodo-pyridine (500 mg, 2.09 mmol) in THF (3 mL)was added dropwise, and the reaction stirred for 30 minutes Iodoethane(0.2 mL, 2.5 mmol) was added, and the reaction was stirred for 1 hour at−78° C., then 1 hour while warming to 0° C. The reaction was quenchedwith sat. NH₄Cl, made basic with saturated NaHCO₃, and extracted withethyl acetate. Organics were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. Purification by silica gel chromatography (20%ethyl acetate/hexanes) gave 429 mg (77%) of4-chloro-3-ethyl-5-iodo-pyridine as a waxy white solid. ¹H NMR (300 MHz,CDCl₃) δ8.78 (s, 1H), 8.33 (s, 1H), 2.83 (q, 2H, J=7.5 Hz), 1.26 (t, 3H,J=7.5 Hz). Anal. (C₇H₇ClIN) C, H, N.

(b) Intermediate46b—5-(4-Chloro-5-ethyl-pyridin-3-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

The title compound was prepared in 69% yield from intermediate 16a and4-chloro-3-ethyl-5-iodo-pyridine similar to the procedure forintermediate 41a. ¹H NMR (300 MHz, CDCl₃) δ8.49 (d, 2H, J=3.3 Hz), 8.06(s, 1H) 7.26-7.69 (m, 9H), 5.79 (s, 2H), 3.65 (t, 2H, J=8.1 Hz), 2.88(q, 2H, J=7.5 Hz), 1.35 (t, 3H, J=7.5 Hz), 0.95 (t, 2H, J=8.1 Hz), −0.03(s, 9H). Anal. (C₂₈H₃₂ClN₃OSi) C, H, N.

(c) Example46—5-(4-Chloro-5-ethyl-pyridin-3-yl)-3-(E)-styryl-1H-indazole

The title compound was prepared in 80% yield by the SEM-deprotection ofintermediate 46b in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.25 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H),8.27 (s, 1H), 7.55-7.72 (m, 5H), 7.26-7.48 (m, 4H), 2.83 (q, 2H, J=7.5Hz), 1.26 (t, 2H, J=7.5 Hz). Anal. (C₂₂H₁₈N₃Cl.0.3 H₂O) C, H, N. MS (ES)[m+H]/z calculated 360, found 360.

EXAMPLE 473-[3-(1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methoxy-phenol

(a) Intermediate47a—3-(1H-Benzoimidazol-2-yl)-5-{2-methoxy-3-{2-(2-trimethylsilanyl-ethoxymethyl)-ethoxy]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

The title compound was prepared in 92% yield from intermediate 7c′ and2-methoxy-3-[2-(2-trimethylsilanyl-ethoxy)-ethoxy]-boronic acid (Foundin: Kania, Braganza, et al., patent application “Compounds andPharmaceutical Compositions for Inhibiting Protein Kinases, and Methodsfor Their Use”, p. 52, line 10 to p. 53, line 26; and p.59, line 16 top. 60, line 4, U.S. Provisional Serial No. 60/142,130, filed Jul. 2,1999, incorporated by reference herein in its entirety.), similar to theprocedure for intermediate 7d′. ¹H NMR (300 MHz, CDCl₃) δ9.92 (s, 1H),8.79 (s, 1H), 7.86-7.89 (m, 1H), 7.79 (dd, 1H, J=8.7, 1.5 Hz), 7.63 (d,1H, J=8.7 Hz), 7.49-7.52 (m, 1H), 7.28-7.31 (m, 3H), 7.19 (dd, 1H,J=8.4, 1.8 Hz), 7.15 (d, 1H, J=7.8 Hz), 5.82 (s, 2H), 5.34 (s, 2H), 3.86(t, 2H, J=8.4 Hz), 3.65 (t, 2H, J=8.1 Hz), 3.59 (s, 3H), 0.92-1.02 (m,4H), 0.02 (s, 9H), −0.03 (s, 9H).

(b) Example47—3-[3-(1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methoxy-phenol

The title compound was prepared in 61% yield by the SEM-deprotection ofintermediate 47a in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.64 (s, 1H), 12.98 (s, 1H), 9.36 (s, 1H),8.59 (s, 1H), 7.68 (dd, 1H, J=8.4, 0.6 Hz), 7.60 (br s, 2H), 7.59 (dd,1H, J=8.4, 1.5 Hz), 7.18-7.22 (m, 2H), 7.03 (t, 1H, J=7.8 Hz), 6.83-6.92(m, 2H), 3.46 (s, 3H). Anal. (C₂₁H₁₆N₄O₂.1.0 H₂O) C, H, N. MS (ES)[m+H]/z calculated 357, found 357; [m−H]/z calculated 355, found 355.

EXAMPLE 48 3-(1H-Benzoimidazol-2-yl)-5-(1H-indol-4-yl)-1H-indazole

(a) Intermediate 48a—4-Bromo-(tert-butyl-dimethyl-silanyl)-1H-indole

Sodium hydride (60% dispersion in mineral oil, 1.84 g, 46 mmol) waswashed with hexanes and then stirred in THF (30 mL) under argon at 0° C.4-Bromoindole (3.0 g, 15.3 mmol) in THF (10 mL) was added slowly, andthe reaction stirred 1 hour while warming to room temperature.tert-Butyl-dimethylsilyl chloride (3.5 g, 23 mmol) was added, and thereaction stirred 16 hours before it was diluted with ether (100 mL) andslowly quenched with H₂O. Organics were separated and washed with brine,dried over Na₂SO₄, and concentrated in vacuo. Purification by silica gelchromatography (5% ether/hexanes) gave 4.28 g (90%) intermediate 48a asa white solid. ¹H NMR (300 MHz, CDCl₃) δ7.44 (d, 1H, J=8.4 Hz), 7.27 (d,1H, J=8.4 Hz), 7.22 (d, 1H, J=3.3 Hz), 7.00 (t, 1H, J=8.1 Hz), 6.67 (dd,1H, J=3.3, 0.9 Hz), 0.92 (s, 9H), 0.60 (s, 6H). Anal. (C₁₄H₂₀BrNSi) C,H, N.

(b) Intermediate 48b—1-(tert-Butyl-dimethyl-silanyl)-1H-indole-4-boronicacid

Intermediate 48a (2.22 g, 7.16 mmol) was stirred in dry THF (15 mL) at−78° C. n-Butyllithium (2.5 M in hexanes, 3.45 mL, 8.6 mmol) was addedslowly. The reaction stirred for 20 minutes before it was transferredvia cannula to a flask of trimethyl borate (8.0 mL, 72 mmol) in dry THF(10 mL) at −78° C. The reaction stirred for 30 minutes at −78° C. andthen 3 hours while warming to room temperature. It was quenched with H₂Oand extracted with ether. Organics were washed with brine, dried overNa₂SO₄, and concentrated in vacuo. Purification by silica gelchromatography (33% ethyl acetate/hexanes) gave 1.28 g (65%) ofintermediate 48b as a white foam. ¹H NMR (300 MHz, DMSO-d₆w/D₂O) δ7.55(d, 1H, J=8.4 Hz), 7.45 (d, 1H, J=8.4 Hz), 7.28 (s, 1H), 7.03-7.09 (m,1H), 6.96 (s, 1H), 0.84 (s, 9H), 0.57 (s, 6H). Anal. (C₁₄H₂₂BNO₂Si-0.9H₂O) C, H, N.

(c) Intermediate48c—3-(1H-Benzoimidazol-2-yl)-5-[1-(tert-butyl-dimethyl-silanyl)-1H-indol-4-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

The title compound was prepared in 95% yield from intermediate 7c′ andintermediate 48b similar to the procedure for intermediate 7d′. ¹H NMR(300 MHz, CDCl₃) δ9.90 (s, 1H), 8.96 (d, 1H, J=0.9 Hz), 7.84-7.90 (m,2H), 7.69 (d, 1H, J=8.7 Hz), 7.48-7.53 (m, 2H), 7.23-7.33 (m, 5H), 6.82(d, 1H, J=3.3 Hz), 5.84 (s, 2H), 3.67 (t, 2H, J=8.1 Hz), 0.96 (s, 9H),0.94 (t, 2H, J=8.1 Hz), 0.65 (s, 6H), −0.03 (s, 9H). Anal.(C₃₄H₄₃N₅OSi₂) C, H, N.

(d) Example 48—3-(1H-Benzoimidazol-2-yl)-5-(1H-indol-4-yl)-1H-indazole

The title compound was prepared in 79% yield by theSEM,TBDMS-deprotection of intermediate 48c in a manner analogous to theprocedure for example 41. ¹H NMR (300 MHz, DMSO-d₆) δ13.66 (s, 1H),12.97 (s, 1H), 11.25 (s, 1H), 8.78 (s, 1H), 7.68-7.81 (m, 3H), 7.51 (d,1H, J=7.2 Hz), 7.42-7.46 (m, 2H), 7.14-7.26 (m, 4H), 6.59 (t, 1H, J=2.1Hz). Anal. (C₂₂H₁₅N₅.0.3 H₂O) C, H, N. MS (ES) [m+H]/z calculated 350,found 350; [m−H]/z calculated 348, found 348.

EXAMPLE 493-[-3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-2,4-difluoro-phenol

(a) Intermediate49a—[2-(2,4-Difluoro-phenoxymethoxy)-ethyl]-trimethyl-silane

2,4-Difluoro-phenol (6.0 g, 46.1 mmol) and DIEA (9.64 mL, 55.3 mmol)were stirred in dry CH₂Cl₂ (100 mL) at room temperature.2-(Trimethylsilyl)ethoxymethyl chloride (9.0 mL, 50.8 mmol) was added,and the reaction stirred 1 for hour The solution was washed with H₂O andbrine, dried over Na₂SO₄, and concentrated in vacuo. Purification bysilica gel chromatography gave 10.88 g (91%) of the title compound as aclear oil. ¹H NMR (300 MHz, CDCl₃) δ7.11-7.20 (m, 1H), 6.74-6.89 (m,2H), 5.20 (s, 2H), 3.77-3.83 (m, 2H), 0.93-0.99 (m, 2H), 0.01 (s, 9H).

(b) Intermediate49b—3-(1H-Benzoimidazol-2-yl)-5{2,6-difluoro-3-[2-(2-trimethylsilanyl-ethoxy-ethoxy]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

Intermediate 49a (1.4 g, 5.38 mmol) was stirred in dry THF (16 mL) underargon at −78° C. n-Butyllithium (2.5 M in hexanes, 2.32 mL, 5.8 mmol)was added dropwise, and the reaction stirred for 20 minutes. Thesolution was then transferred via cannula to a flask of dry zincchloride under argon at room temperature. After 30 minutes intermediate7c′ (320 mg, 0.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (60mg, 0.05 mmol) were added, and the reaction stirred at room temperaturefor 2 hours The solution was diluted with ether and washed with H₂O,saturated NaHCO₃, and brine. Organics were dried over Na₂SO₄ andconcentrated in vacuo. Purification by silica gel chromatography (20% to30% Et₂O/hexanes) gave 372 mg (92%) of the title compound as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ9.89 (s, 1H), 8.80 (s, 1H), 7.86-7.89(m, 1H), 7.70 (dd, 1H, J=8.7, 0.9 Hz), 7.58 (dd, 1H, J=8.7, 1.2 Hz),7.49-7.53 (m, 1H), 7.17-7.31 (m, 3H), 6.90-6.97 (m, 1H), 5.82 (s, 2H),5.28 (s, 2H), 3.86 (t, 2H, J=8.4 Hz), 3.67 (t, 2H, J=8.1 Hz), 0.92-1.04(m, 4H), 0.02 (s, 9H), −0.02 (s, 9H). Anal. (C₃₂H₄₀F₂N₄O₃Si₂.0.25 H₂O)C, H, N.

(c) Example49—3-[-3(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-2,4-difluoro-phenol

The title compound was prepared in 70% yield by the SEM-deprotection ofintermediate 49b in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.75 (s, 1H), 13.00 (s, 1H), 9.88 (s, 1H),8.56 (s, 1H), 7.70-7.78 (m, 2H), 7.48-7.53 (m, 2H), 7.17-7.25 (m, 2H),6.99-7.05 (m, 2H). Anal. (C₂₀H₁₂FN₄O.0.33 H₂O) C, H, N. MS (ES) [m+H]/zcalculated 363, found 363; [m−H]/z calculated 361, found 361.

EXAMPLE 504-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-3,5-difluoro-phenolEXAMPLE 512-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-3,5-difluoro-phenol

(a) Intermediate50a—[2-(3,5-Difluoro-phenoxymethoxy)-ethyl]-trimethyl-silane

The title compound was prepared in 94% yield from 3,5-difluorophenolanalogous to the procedure to intermediate 49a. ¹H NMR (300 MHz, CDCl₃)δ6.55-6.60 (m, 2H), 6.40-6.48 (m, 1H), 5.18 (s, 2H), 3.70-3.76 (m, 2H),0.92-0.98 (m, 2H), 0.01 (s, 9H).

(b) Intermediate mixture 50b and50c—3-(1H-Benzoimidazol-2-yl)-5{2,6-difluoro-4-[2-(2-trimethylsilanyl-ethoxy-ethoxy]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleand3-(1H-Benzoimidazol-2-yl)-5{2,4difluoro-6-[2-(2-trimethylsilanyl-ethoxy-ethoxy]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

The title compounds were prepared in 52% yield as an inseparable mixturefrom intermediate 50a similar to the procedure for intermediate 49b. ¹HNMR (300 MHz, CDCl₃) δ9.89 (s, 1H), 8.44-8.75 (m, 1H), 7.83-7.93 (m,1H), 7.45-7.69 (m, 3H), 7.26-7.39 (m, 2.5H), 6.58-6.88 (m, 1.5H), 5.81(s, 1H), 5.80 (s, 1H), 5.26 (s, 1H), 5.13 (s, 1H), 3.57-3.82 (m, 4H),0.86-1.04 (m, 4H), −0.06-0.02 (m, 18H).

(c) Example50—4-[-3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-3,5-difluoro-phenol

The title compound was prepared in 36% yield by the SEM-deprotection ofintermediate mixture 50b and 50c in a manner analogous to the procedurefor example 41. ¹H NMR (300 MHz, DMSO-d₆) δ13.73 (s, 1H), 13.01 (s, 1H),10.50 (s, 1H), 8.50 (s, 1H), 7.70-7.74 (m, 2H), 7.43-7.52 (m, 2H),7.15-7.25 (m, 2H), 6.62 (dd, 2H, J=13.8, 1.5 Hz). Anal. (C₂₀H₁₂FN₄O.0.7H₂O) C, H, N. MS (ES) [m+H]/z calculated 363, found 363; [m−H]/zcalculated 361, found 361.

(d) Example51—2-[-3(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-3,5-difluoro-phenol

The title compound was prepared in 40% yield by the SEM-deprotection ofintermediate mixture 50b and 50c in a manner analogous to the procedurefor example 41. ¹H NMR (300 MHz, DMSO-d₆) δ13.65 (s, 1H), 12.98 (s,1H),10.39 (s, 1H), 8.47 (s, 1H), 7.66-7.72 (m, 2H), 7.50 (d, 1H, J=7.2Hz), 7.40 (d, 1H, J=8.4 Hz), 7.14-7.24 (m, 2H), 6.73-6.80 (m, 1H), 6.64(d, 1H, J=10.5 Hz). Anal. (C₂₀H₁₂FN₄O. 0.9 H₂O) C, H, N. MS (ES) [m+H]/zcalculated 363, found 363; [m−H]/z calculated 361, found 361.

EXAMPLE 523-(1H-Benzoimidazol-2-yl)-5-(4-chloro-pyridin-3-yl)-1H-indazole

(a) Intermediate52a—3-(1H-Benzoimidazol-2-yl)-5-(4-chloro-pyridin-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

The title compound was prepared in 88% yield from intermediate 25a and4-chloro-3-iodo-pyridine similar to the procedure for intermediate 41 a.¹H NMR (300 MHz, CDCl₃) δ9.96 (s, 1H), 8.77 (s, 1H), 8.72 (s, 1H), 8.53(d, 1H, J=5.4 Hz), 7.85-7.89 (m, 1H), 7.72 (dd, 1H, J=8.7, 0.9 Hz), 7.61(dd, 1H, J=8.7, 1.5 Hz), 7.50-7.53 (m, 1H), 7.47 (d, 1H, J=5.4 Hz),7.28-7.35 (m, 2H), 5.84 (s, 2H), 3.65 (t, 2H, J=8.1 Hz), 0.95 (t, 2H,J=8.1 Hz), −0.03 (s, 9H).

(b) Example52—3-(1H-Benzoimidazol-2-yl)-5-(4-chloro-pyridin-3-yl)-1H-indazole

The title compound was prepared in 54% yield by the SEM-deprotection ofintermediate 52a in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.81 (s, 1H), 13.02 (s, 1H), 8.70 (s, 1H),8.56-8.60 (m, 2H), 8.22 (s, 1H), 7.55-7.80 (m, 5H), 7.20 (d, 5H,J=3.6Hz). Anal. (C₂₂H₁₈CIN₃.0.5 H₂O) C, H, N. MS (ES) [m+H]/z calculated346, found 346.

EXAMPLE 535-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]4-methyl-[3,4′]bipyridinyl

(a) Intermediate 53a—5-(Bromo-4-methyl-[3,4′]bipyridinyl

3,5-Dibromo-4-methyl-pyridine (2.21 g, 8.8 mmol), 4-pyridylboronic acid(1.08 g, 8.8 mmol) and potassium phosphate (2.8 g, 13.2 mmol) werestirred in DMA (50 mL)/H₂O (6 mL) in a flask purged with argon.Tetrakis(triphenylphosphine)palladium (0) (812 mg, 0.7 mmol) was added,and the reaction stirred at 92° C. under argon for 16 hours. Thesolution was concentrated in vacuo, and the residue was dissolved inethyl acetate. Organics were washed with H₂O and brine, dried (Na₂SO₄),and concentrated in vacuo. Purification by silica gel chromatography(40% to 50% ethyl acetate/hexanes) gave 1.14 g (60%) of intermediate 53aas a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.73 (dd, 2H, J=4.5, 1.5 Hz),8.72 (s, 1H), 8.32 (s, 1H), 7.25 (dd, 2H, J=4.5, 1.5 Hz), 2.35 (s, 3H).Anal. (C₁₁H₉BrN₂) C, H, N.

(b) Intermediate53b—5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-4-methyl-[3,4′]bipyridinyl

The title compound was prepared in 64% yield from intermediate 25a andintermediate 53a similar to the procedure for intermediate 41a. ¹H NMR(300 MHz, CDCl₃) δ10.21 (s, 1H), 8.70-8.76 (m, 3H), 8.61 (s, 1H), 8.46(s, 1H), 7.85-7.88 (m, 1H), 7.72 (dd, 1H, J=8.7, 0.9 Hz), 7.47-7.53 (m,2H), 7.24-7.37 (m, 4H), 5.84 (s, 2H), 3.64 (t, 2H, J=8.1 Hz), 2.19 (s,3H), 0.94 (t, 2H, J=8.1 Hz), −0.04 (s, 9H).

(c) Example53—5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-[3,4′]bipyridinyl

The title compound was prepared in 71% yield by the SEM-deprotection ofintermediate 53b in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.79 (s, 1H), 13.02 (s, 1H), 8.71 (d, 2H,J=4.8 Hz), 8.55 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 7.78 (d, 1H, J=8.7Hz), 7.52-7.58 (m, 5H), 7.18-7.21 (m, 2H), 2.17 (s, 3H). Anal.(C₂₅H₁₈N₆.0.75 H₂O) C, H, N. MS (ES) [m+H]/z calculated 403, found 403;[m−H]/z calculated 401, found 401.

EXAMPLE 545-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-1,2,3,4,4a,8a-hexahydro-[1,7]naphthyridine

(a) Intermediate 54a—3-(3,5-Dibromo-pyridin-4-yl)-propylamine

LDA was prepared by the addition of n-butyllithium (2.5 M in hexanes,6.8 mL, 17.0 mmol) to a solution of diisopropylamine (2.5 mL, 17.8 mmol)in THF (40 mL) at −20° C. After 10 minutes, the solution was cooled to−78° C. 3,5-Dibromopyridine (3.84 g, 16.2 mmol) in THF (25 mL) was addeddropwise, and the reaction stirred for 30 minutes1-(3-Bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentate (5 g,17.8 mmol) was added, and the reaction stirred for 1 hour at −78° C. andthen for 1 hour while warming to 0° C. The reaction was quenched withsat. NH₄Cl, made basic with saturated NaHCO₃, and extracted with ethylacetate. Organics were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. Purification by silica gel chromatography (15%MeOH/CHCl₃) gave 2.72 g (54%) of intermediate 54a as a light brown oil.¹H NMR (300 MHz, CDCl₃) δ8.55 (d, 2H), 2.72-3.05 (m, 6H), 1.70-1.77 (m,2H).

(b) Intermediate 54b—2-Trimethylsilanyl-ethanesulfonic acid[3-(3,5-dibromo-pyridin-4-yl)-propyl]-amide

Intermediate 54a (2.7 g, 9.2 mmol) was stirred with triethylamine (1.92mL, 13.8 mmol) in dry DMF (20 mL) at 0° C.2-Trimethylsilyanyl-ethanesulfonyl chloride, SES-CI, (see Weinreb etal., Tet. Lett. 27, 19, 1986, 2099-2102) (1.9 g, 9.5 mmol) was addedslowly, and the reaction stirred for 1.5 hours at 0° C. The reaction wasdiluted with H₂O and extracted with ether. Organics were washed withbrine, dried over Na₂SO₄, and concentrated in vacuo. Purification bysilica gel chromatography (33% ethyl acetate/hexanes) gave 2.37 g (56%)of intermediate 54b as a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.58 (s,2H), 4.36 (t, 1H, J=6.3 Hz), 3.26 (q, 2H, J=6.3 Hz), 2.93-3.06 (m, 4H),1.81-1.89 (m, 2H), 1.00-1.07 (m, 2H), 0.07 (s, 9H). Anal.(C₁₃H₂₂Br₂N₂O₂SSi) C, H, N, S.

(c) Intermediate 54c—5-Bromo-1-(2-trimethylsilanyl-ethanesulfonyl)-1,2,3,4-tetrahydro-[1,7]naphthyridine

Intermediate 54b (860 mg, 1.88 mmol) and potassium carbonate (390 mg,2.82 mmol) were stirred in dry toluene (15 mL) in a flask purged withargon. Tetrakis(triphenylphosphine)palladium (0) (218 mg, 0.19 mmol) wasadded, and the reaction stirred under argon at 102° C. for 48 hours. Thereaction was diluted with ethyl acetate and washed with brine, dried(Na₂SO₄), and concentrated in vacuo. Purification by silica gelchromatography (25% ethyl acetate/hexanes) gave 372 mg (52%) ofintermediate 54c as a waxy white solid. ¹H NMR (300 MHz, CDCl₃) δ8.70(s, 1H), 8.42 (s, 1H), 3.72-3.76 (m, 2H), 3.07-3.14 (m, 2H), 2.83 (t,2H, J=6.9 Hz), 2.07-2.12 (m, 2H), 1.04-1.11 (m, 2H), 0.05 (s, 9H). Anal.(C₁₃H₂₁BrN₂O₂SSi) C, H, N, S.

(d) Intermediate54d—5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanl-ethoxymethyl)-1H-indazol-5-yl]-1-(2-trimethylsilanyl-ethanesulfonyl)-1,2,3,4,4a,8a-hexahydro-[1,7]naphthyridine

The title compound was prepared in 51% yield from intermediate 25a andintermediate 54c similar to the procedure for intermediate 41a. ¹H NMR(300 MHz, CDCl₃) δ10.36 (s, 1H), 8.88 (s, 1H), 8.64 (t, 1H, J=0.9 Hz),8.29 (s, 1H), 3.82-3.86 (m, 1H), 7.69 (dd, 1H, J=8.7, 0.9 Hz), 7.50-7.52(m, 1H), 7.41 (dd, 1H, J=8.7, 1.5 Hz), 7.26-7.33 (m, 2H), 5.83 (s, 2H),3.80 (t, 2H, J=5.7 Hz), 3.63 (t, 2H, J=8.1 Hz), 3.13-3.20 (m, 2H), 2.72(t, 2H, J=6.6 Hz), 1.93-1.99 (m, 2H), 1.10-1.16 (m, 2H), 0.94 (t, 2H,J=8.1 Hz), 0.09 (s, 9H), −0.05 (s, 9H).

(e) Example54—5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-1,2,3,4,4a,8a-hexahydro-[1,7]naphthyridine

The title compound was prepared in 64% yield by the SEM,SES-deprotection of intermediate 54d in a manner analogous to theprocedure for example 41. ¹H NMR (300 MHz, DMSO-d₆) δ13.71 (s, 1H),13.00 (s, 1H), 8.41 (s, 1H), 7.82 (s, 1H), 7.69 (d, 2H, J=8.7 Hz), 7.63(s, 1H), 7.50 (d, 1H, J=7.2 Hz), 7.44 (dd, 1H, J=8.7, 1.5 Hz), 7.16-7.22(m, 2H), 6.11 (s, 1H), 3.23 (br s, 2H), 2.55 (t, 2H, J=6.0 Hz),1.68-1.73 (m, 2H). Anal. (C₂₂H₁₈N₆.0.45 H₂O) C, H, N. MS (ES) [m+H]/zcalculated 366, found 366.

EXAMPLE 55N-{4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinolin-8-yl}-nicotinamide

(a) Intermediate 55a—N-(4-Bromo-isoquinolin-8-yl)-nicotinamide

8-Amino-4-bromo-isoquinoline (328 mg, 1.47 mmol), triethylamine (820 μL,5.9 mmol), and DMAP (10 mg) were stirred in CH₂Cl₂ (50 mL). Nicotinoylchloride, hydrochloride (395 mg, 2.2 mmol) was added, and the reactionstirred at reflux for 18 hours. The reaction was concentrated in vacuoand purified by silica gel chromatography (3% MeOH/ethyl acetate) togive 272 mg (56%) of intermediate 55a as a white solid. ¹H NMR (300 MHz,CDCl₃) δ10.95 (s, 1H), 9.46 (s, 1H), 9.25 (d, 1H, J=1.5 Hz), 8.81 (dd,2H, J=4.8, 1.5 Hz), 8.40-8.45 (m, 1H), 7.92-8.06 (m, 3H), 7.59-7.64 (m,1H). Anal. (C₁₅H₁₀BrN₃O) C, H, N.

(b) Intermediate55b—N-(4-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethyoxymethyl)-1H-indazol-5-yl]-isoquinolin-8-yl}-nicotinamide

The title compound was prepared in 76% yield from intermediate 25a andintermediate 55a similar to the procedure for intermediate 41a. ¹H NMR(300 MHz, CDCl₃) δ10.27 (s, 1H), 9.48 (s, 1H), 9.29 (d, 1H, J =1.8 Hz),8.83-8.88 (m, 2H), 8.79 (s, 1H), 8.58 (s, 1H), 8.36 (d, 1H, J=7.8 Hz),8.02 (d, 1H, J=6.9 Hz), 7.73-7.81 (m, 3H), 7.58-7.65 (m, 2H), 7.47-7.53(m, 2H), 7.24-7.29 (m, 2H), 5.86 (s, 2H), 3.67 (t, 2H, J=8.1 Hz), 0.96(t, 2H, J=8.1 Hz), −0.04 (s, 9H).

(c) Example55—N-{(4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinolin-8-yl}-nicotinamide

The title compound was prepared in 78% yield by the SEM-deprotection ofintermediate 55b in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.85 (s, 1H), 13.04 (s, 1H), 10.98 (s, 1H),9.54 (s, 1H), 9.30 (d, 2H, J=1.8 Hz), 8.83 (dd, 1H, J=4.8, 1.8 Hz), 8.65(s, 1H), 8.59 (s, 1H), 8.45-8.50 (m, 4H), 7.52-7.66 (m, 4H), 7.18 (br s,2H). Anal. (C₂₉H₁₉N₇O0.5 H₂O) C, H, N. MS (ES) [m+H]/z calculated 482,found 482.

EXAMPLE 56N-{4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinolin-8-yl}-acetamide

(a) Intermediate 56a—N-(4Bromo-isoquinolin-8-yl)-acetamide

8-Amino-4-bromo-isoquinoline (300 mg, 1.35 mmol), DIEA (0.94 mL, 5.38mmol), and acetic anhydride (255 μL, 2.7 mmol) were stirred inchloroform (20 mL) at reflux for 16 hours. The solution was washed withH₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The residuewas stirred in ethanol (6 mL) with HOAc (2 mL) at 72° C. for 20 hours.The solution was allowed to cool and was diluted with ethyl acetate.Organics were washed with 1 N NaOH and brine, dried (MgSO₄), andconcentrated in vacuo. Purification by silica gel chromatography (ethylacetate) gave 232 mg (65%) of intermediate 56a as a white solid. ¹H NMR(300 MHz, CDCl₃) δ10.31 (s, 1H), 9.47 (s, 1H), 8.77 (s, 1H), 7.90-7.97(m, 3H), 2.21 (s, 3H). Anal. (C₁₁H₉BrN₂O) C, H, N.

(b) Intermediate56b—N-{4-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethyoxymethyl)-1H-indazol-5-yl]-isoquinolin-8-yl}-acetamide

The title compound was prepared in 80% yield from intermediate 25a andintermediate 56a similar to the procedure for intermediate 41a. ¹H NMR(300 MHz, CDCl₃) δ10.39 (s, 1H), 9.46 (s, 1H), 8.76 (s, 1H), 8.53 (s,1H), 8.42 (s, 1H), 7.91 (d, 1H, J=7.2 Hz), 7.89 (d, 1H, J=7.2 Hz),7.62-7.72 (m, 3H), 7.48-7.57 (m, 3H), 7.24-7.28 (m, 1H), 5.83 (s, 2H),3.65 (t, 2H, J=8.1 Hz), 2.35 (s, 3H), 0.95 (t, 2H, J=8.1 Hz), −0.04 (s,9H).

(c) Example56—N-{4-[3-(1H-Benzoimidazol-2-yl)1H-indazol-5-yl]-isoquinolin-8-yl}-acetamide

The title compound was prepared in 68% yield by the SEM-deprotection ofintermediate 56b in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.84 (s, 1H), 13.03 (s, 1H), 10.34 (s, 1H),9.56 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 7.82-7.89 (m, 2H), 7.74 (t,1H, J=7.2 Hz), 7.59-7.66 (m, 3H), 7.51 (d, 1H, J=7.2 Hz), 7.13-7.21 (m,2H), 2.25 (s, 3H). Anal. (C₂₅H₁₈N₆O.0.4 H₂O) C, H, N. MS (ES) [m+H]/zcalculated 419, found 419.

EXAMPLE 57N-{4-[3-(1H-Benzoimidazol-2-yl)1H-indazol-5-yl]-isoquinolin-8-yl}-benzyl-amine

(a) Intermediate 57a—Benzyl-(4-bromo-isoquinoline-8-yl)-amine

8-Amino-4-bromo-isoquinoline (220 mg, 0.99 mmol) and benzaldehyde (110μL, 1.1 mmol) were stirred in ethanol (15 mL)/HOAc (0.2 mL) at refluxfor 24 hours. The reaction was cooled to 0° C., and sodiumcyanoborohydride (622 mg, 9.9 mmol) was added in portions. Afterstirring for 1 hour, the reaction was diluted with H₂O and extractedwith ethyl acetate. Organics were washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by silica gel chromatography (33%ethyl acetate/hexanes) gave 136 mg (44%) of intermediate 57a as a lightyellow solid. ¹H NMR (300 MHz, CDCl₃) δ9.61 (s, 1H), 8.64 (s, 1H), 7.79(t, 1H, J=5.7 Hz), 7.55 (t, 1H, J=8.1 Hz), 7.28-7.42 (m, 4H), 7.15-7.24(m, 2H), 6.58 (d, 1H, J=8.4 Hz), 4.53 (d, 2H, J=5.7 Hz). Anal.(C₁₆H₁₃BrN₃) C, H, N.

(b) Intermediate57b—N-{4-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethyoxymethyl)-1H-indazol-5-yl]-isoquinolin-8-yl}-benzyl-amine

The title compound was prepared in 72% yield from intermediate 25a andintermediate 57a similar to the procedure for intermediate 41a. ¹H NMR(300 MHz, CDCl₃) δ10.02 (s, 1H), 9.38 (s, 1H), 8.82 (s, 1H), 8.56 (s,1H), 7.82 (d, 1H, J=8.7 Hz), 7.73 (d, 1H, J=8.7 Hz), 7.63 (dd, 1H,J=8.4, 1.5 Hz), 7.24-7.52 (m, 9H), 7.17 (d, 1H, J=8.4 Hz), 6.69 (d, 1H,J=7.5 Hz), 5.86 (s, 2H), 5.23 (s, 1H), 4.58 (d, 2H, J=4.5 Hz), 3.67 (t,2H, J=8.1 Hz), 0.97 (t, 2H, J=8.1 Hz), −0.03 (s, 9H).

(c) Example57—N-{4-[3-(1H-Benzoimidazol-2-yl)1H-indazol-5-yl]-isoquinolin-8-yl}-benzyl-amine

The title compound was prepared in 72% yield by the SEM-deprotection ofintermediate 57b in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.80 (s, 1H), 13.01 (s, 1H), 9.71 (s, 1H),8.56 (s, 1H), 8.42 (s, 1H), 7.71-7.81 (m, 2H), 7.30-7.63 (m, 8H),7.17-7.25 (m, 3H), 6.90 (d, 1H, J=7.2 hz), 6.52 (d, 1H, J=7.2 Hz), 4.57(d, 2H, J=5.4 Hz). Anal. (C₃₀H₂₂N₆.0.5 H₂O) C, H, N. MS (ES) [m+H]/zcalculated 467, found 467.

EXAMPLE 583-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-[3,3′]bipyridinyl

(a) Intermediate 58a—5-Bromo-4-methyl-[3,3′]bipyridinyl

The title compound was prepared in 54% yield from3,5-dibromo-4-methyl-pyridine and 3-pyridyl boronic acid analogous tothe procedure for intermediate 53a. ¹H NMR (300 MHz, CDCl₃) δ8.67-8.71(m, 2H), 8.59 (dd, 1H, J=2.4, 0.6 Hz), 8.33 (s, 1H), 7.62-7.66 (m, 1H),7.39-7.44 (m, 1H), 2.35 (m, 3H). Anal. (C₁₁H₉BrN₂.0.1 H₂O) C, H, N.

(b) Intermediate58b—3-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-4-methyl-[3,3′]bipyridinyl

The title compound was prepared in 37% yield from intermediate 25a andintermediate 58a analogous to the procedure for intermediate 41a. ¹H NMR(300 MHz, CDCl₃) δ10.24 (s, 1H), 8.68-8.71 (m, 3H), 8.61 (s, 1H), 8.47(s, 1H), 7.85-7.88 (m, 1H), 7.70-7.78 (m, 2H), 7.42-7.53 (m, 3H),7.26-7.33 (m, 2H), 5.83 (s, 2H), 3.64 (t, 2H, J=8.1 Hz), 2.19 (s, 3H),0.95 (t, 2H, J=8.1 Hz), −0.05 (s, 9H).

(c) Example58—3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-[3,3′]bipyridinyl

The title compound was prepared in 74% yield by the SEM-deprotection ofintermediate 58b in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.79 (s, 1H), 13.02 (s, 1H), 8.72 (d, 1H,J=1.5 Hz), 8.65 (dd, 1H, J=4.8, 1.5 Hz), 8.54 (s, 1H), 8.52 (s, 1H),8.48 (s, 1H), 7.96-8.00 (m, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.69 (d, 1H,J=7.5 Hz), 7.49-7.57 (m, 3H), 7.17-7.23 (m, 2H), 2.16 (s, 3H). Anal.(C₂₅H₁₈N₆.0.6 H₂O) C, H, N. MS (ES) [m+H]/z calculated 403, found 403.

EXAMPLE 59(E)-3-{5-[3-(1H-Benzoimidazol-2-yl)1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-prop-2en-1-oland EXAMPLE 60(E)-3-{5-[3-(1-H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-propan-1-ol

(a) Intermediate 59a—5-Bromo-4-methyl-pyridine-3-carbaldehyde

3,5-Dibromo-4-methyl-pyridine (3.8 g, 15.1 mmol) was stirred in dry THF(150 mL) at −100° C. (N₂/ether) under argon. n-Butyllithium (2.5 M inhexanes, 6.2 mL, 15.4 mmol) was added dropwise, and the reaction stirredfor 5 minutes DMF (1.8 mL, 23.2 mmol) was added, and the reaction wasstirred for 20 minutes at −100° C. and then for 1 hour at −78° C. Thereaction was quenched with sat. NH₄Cl and extracted with ether. Organicswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo.Purification by silica gel chromatography (20% ethyl acetate/hexanes)gave 2.18 g (72%) of intermediate 59a as a clear oil which slowlysolidified. ¹H NMR (300 MHz, CDCl₃) δ10.25 (s, 1H), 8.84 (s, 1H), 8.83(s, 1H), 2.76 (s, 3H). Anal. (C₇H₆BrNO) C, H, N.

(b) Intermediate 59b—(E)-3-(5-Bromo-4-methyl-pyridin-3-yl)-acrylic AcidEthyl Ester

Intermediate 59a (690 mg, 3.45 mmol), ethyl hydrogen malonate (600 mg,4.5 mmol), and piperidine (170 μL, 1.73 mmol) were refluxed in pyridine(5 mL) for 7 hours The reaction was concentrated in vacuo and purifiedby silica gel chromatography (20% ethyl acetate/hexanes) to give 560 mg(60%) of intermediate 59b as a waxy white solid. ¹H NMR (300 MHz, CDCl₃)δ8.65 (s, 1H), 8.57 (s, 1H), 7.87 (d, 1H, J=15.9 Hz), 6.39 (d, 1H,J=15.9 Hz), 4.29 (q, 2H, J=7.2 Hz), 2.50 (s, 3H), 1.35 (t, 3H, J=7.2Hz). Anal. (C₁H₁₂BrNO₂) C, H, N.

(c) Intermediate59c—(E)-3-{5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-acrylicAcid Ethyl Ester

The title compound was prepared in 83% yield from intermediate 25a andintermediate 59b similar to the procedure for intermediate 41a. ¹H NMR(300 MHz, CDCl₃) δ10.00 (s, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.55 (s,1H), 7.99 (d, 1H, J=15.9 Hz), 7.83-7.87 (m, 1H), 7.71 (d, 1H, J=8.7 Hz),7.50-7.53 (m, 1H), 7.43 (dd, 1H, J =8.7, 1.5 Hz), 7.27-7.32 (m, 2H),6.50 (d, 1H, J=15.9 Hz), 5.84 (s, 2H), 4.31 (q, 2H, J=7.2 Hz), 3.65 (t,2H, J=8.1 Hz), 2.36 (s, 3H), 1.37 (t, 3H, J=7.2 Hz), 0.95 (t, 2H, J=8.1Hz), −0.04 (s, 9H).

(d) Intermediate59d—(E-3-{5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-prop-2-en-1-ol

A solution of intermediate 59c (402 mg, 0.73 mmol) in ether (10 mL) wasadded dropwise to a stirred suspension of LAH (180 mg, 4.74 mmol) inether (10 mL) at 0° C. The reaction was allowed to stir for 3 hourswhile warming to room temperature. The reaction was quenched with waterand extracted with ethyl acetate. Organics were washed with brine, driedover Na₂SO₄, and concentrated in vacuo. Purification by silica gelchromatography (50% to 100% ethyl acetate/hexanes) gave 72 mg (19%) ofintermediate 59d as a white foam (followed by 186 mg (50%) ofintermediate 59e). ¹H NMR (300 MHz, CDCl₃) δ9.99 (s, 1H), 8.64 (s, 1H),8.63 (s, 1H), 8.45 (s, 1H), 7.83-7.87 (m, 1H), 7.69 (d, 1H, J=8.7 Hz),7.50-7.53 (m, 1H), 7.43 (dd, 1H, J=8.7, 1.5 Hz), 7.26-7.32 (m, 2H), 6.86(d, 1H, J=15.9 Hz), 6.33-6.41 (m, 1H), 5.84 (s, 2H), 4.42 (br s, 2H),3.65 (t, 2H, J=8.1 Hz), 2.28 (s, 3H), 1.73 (br, s, 1H), 0.95 (t, 2H,J=8.1 Hz), −0.04 (s, 9H).

(e) Intermediate59e—(E)-3-{5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-propan-1-ol

See the procedure for intermediate 59d above. ¹H NMR (300 MHz, CDCl₃)δ10.17 (s, 1H), 8.63 (s, 1H), 8.40 (s, 2H), 7.83-7.87 (m, 1H), 7.68 (d,1H, J=8.7 Hz), 7.49-7.52 (m, 1H), 7.43 (dd, 1H, J=8.7, 1.5Hz), 7.26-7.31(m, 2H), 5.83 (s, 2H), 3.77 (t, 2H, J=6.3 Hz), 3.65 (t, 2H, J=8.1 Hz),2.82 (t, 2H, J=7.5 Hz), 2.24 (s, 3H), 1.88-1.95 (m, 2H), 1.74 (br s,1H), 0.94 (t, 2H, J=8.1 Hz), −0.05 (s, 9H).

(f) Example59—(E)-3-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-prop-2-en-1-ol

The title compound was prepared in 50% yield by the SEM-deprotection ofintermediate 59d in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.78 (s, 1H), 13.02 (s, 1H), 8.63 (s, 1H),8.43 (s, 1H), 8.35 (s, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.63 (br.s, 1H),7.55 (br s, 1H), 7.46 (dd, 1H, J=8.7, 1.5 Hz), 7.20 (br s, 2H), 6.83 (d,1H, J=15.9 Hz), 6.37-6.46 (m, 1H), 4.99 (t, 1H, J=5.4 Hz), 4.19 (s, 2H),2.23 (s, 3H). Anal. (C₂₃H₁₉N₅O.0.6 H₂O) C, H, N. MS (ES) [m+H]/zcalculated 382, found 382.

(g) Example60—(E)-3-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-propan-1-ol

The title compound was prepared in 62% yield by the SEM-deprotection ofintermediate 59e in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.77 (s, 1H), 13.02 (s, 1H), 8.41 (s, 1H),8.37 (s, 1H), 8.30 (s, 1H), 7.73 (d, 1H, J=8.7 Hz), 7.67 (br.s, 1H),7.52 (br s, 1H), 7.44 (dd, 1H, J=8.7, 1.5 Hz), 7.19 (br s, 2H), 4.57 (t,1H, J=5.1 Hz), 3.49 (q, 2H, J=6.0 Hz), 2.74 (t, 2H, J=7.8 Hz), 2.21 (s,3H), 1.69-1.79 (m, 2H). Anal. (C₂₃H₂₁N₅O.0.5 H₂O) C, H, N. MS (ES)[m+H]/z calculated 384, found 384.

EXAMPLE 615-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl-4-ethyl-(3,4′]bipyridinyl

(a) Intermediate 61a—3,5-Dibromo-4-ethyl-pyridine

The title compound was prepared in 74% yield by the substitution ofiodoethane for iodomethane in the procedure for the preparation of3,5-dibromo-4-methyl-pyridine (see Gu, et al., Tet. Lett., 37, 15, 1996,2565-2568). ¹H NMR (300 MHz, CDCl₃) δ8.49 (s, 2H), 2.92 (q, 2H, J=7.5Hz), 1.12 (t, 3H, J=7.5 Hz).

(b) Intermediate 61b—5-(Bromo-4-ethyl-[3,4′]bipyridinyl

The title compound was prepared in 51% yield from intermediate 61a and4-pyridyl boronic acid similar to the procedure for intermediate 53a. ¹HNMR (300 MHz, CDCl₃) δ8.71-8.74 (m, 3H), 8.28 (s, 1H), 7.24 (dd, 2H,J=4.5, 1.5 Hz), 2.70 (q, 2H, J=7.5 Hz), 1.10 (t, 3H, J=7.5 Hz). Anal.(C₁₂H₁₁BrN₂) C, H, N. MS (ES) [m+H]/z calculated 263/265, found 263/265.

(c) Intermediate61c—5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-4-ethyl-[3,4′]bipyridinyl

Intermediate 61b (188 mg, 0.71 mmol), intermediate 25a (385 mg, 0.79mmol) and potassium phosphate (226 mg, 1.06 mmol) were stirred in DMA (6mL)/H₂O (0.8 mL) in a flask purged with argon.Tetrakis(triphenylphosphine)palladium (0) (82 mg, 0.07 mmol) was added,and the reaction stirred at 92° C. under argon for 16 hours The solutionwas diluted with ethyl acetate, washed with H₂O and brine, dried overNa₂SO₄, and concentrated in vacuo. Purification by silica gelchromatography (75% to 100% ethyl acetate/hexanes) gave 232 mg (60%) ofintermediate 61c as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ10.18 (s, 1H),8.71-8.75 (m, 3H), 8.57 (s, 1H), 8.41 (s, 1H), 7.84-7.87 (m, 1H), 7.71(d, 1H, J=8.1 Hz), 7.48-7.53 (m, 2H), 7.36 (dd, 2H, J=4.5, 1.5 Hz),7.26-7.32 (m, 2H), 5.84 (s, 2H), 3.65 (t, 2H, J=8.1 Hz), 2.64 (q, 2H,J=7.5 Hz), 0.94 (t, 2H, J=8.1 Hz), 0.77 (t, 3H, J=7.5 Hz), −0.04 (s,9H).

(d) Example61—5-[3-(1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-4-ethyl-[3,4′]bipyridinyl

The title compound was prepared in 61% yield by the SEM-deprotection ofintermediate 61c in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.79 (s, 1H), 13.02 (s, 1H), 8.71 (dd, 2H,J=4.5, 1.5Hz), 8.51 (s, 2H), 8.40 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.68(d, 1H, J=7.5 Hz), 7.49-7.56 (m, 4H), 7.14-7.25 (m, 2H), 2.59 (q, 2H,J=7.5 Hz), 0.69 (t, 3H, J=7.5 Hz). Anal. (C₂₆H₂₀N₆.0.3 H₂O) C, H, N. MS(ES) [m+H]/z calculated 417, found 417.

EXAMPLE 623-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-[2,3′]bipyridinyl

(a) Intermediate62a—3-(1H-Benzoimidazol-2-yl)-5-iodo-1-(4-methoxy-benzyl)-1H-indazole

The title compound was prepared in 59% yield from intermediate 19d andphenylenediamine similar to the procedure for intermediate 7c′. ¹H NMR(300 MHz, DMSO-d₆) δ13.06 (s, 1H), 8.91 (s, 1H), 7.70-7.78 (m, 3H), 7.51(dd, 1H, J=6.3, 2.1 Hz), 7.19-7.28 (m, 4H), 6.88 (dd, 2H, J=6.6, 2.1Hz), 5.72 (s, 2H), 3.69 (s, 3H). Anal. (C₂₂H₁₇IN₄O) C, H, N.

(b) Intermediate62b—3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indazole

The title compound was prepared in 73% yield from intermediate 62a in amanner analogous to the preparation of intermediate 19e. ¹H NMR (300MHz, DMSO-d₆) δ13.03 (s, 1H), 8.93 (d, 1H, J=4.2 Hz), 7.78-7.84 (m, 2H),7.73 (dd, 1H, J=8.7, 0.9 Hz), 7.51 (d, 1H, J=7.2 Hz), 7.20-7.27 (m, 4H),6.87 (d, 2H, J=8.7 Hz), 5.74 (s, 2H), 3.68 (s, 3H), 1.34 (s, 12H). Anal.(C₂₈H₂₉BN₄O₃) C, H, N.

(c) Intermediate 62c—5′-Bromo-4′-methyl-[2,3′]bipyridinyl

3,5-Dibromo-4-methyl-pyridine (2.0 g, 7.8 mmol) and2-tributylstannanyl-pyridine (2.4 g, 6.5 mmol) were stirred in dioxane(20 mL) in a flask purged with argon.Tetrakis(triphenylphosphine)-palladium(0) (600 mg, 0.5 mmol) was added,and the reaction stirred at 100° C. for 80 hours. The solution wasconcentrated in vacuo and purified by silica gel chromatography (30% to50% ethyl acetate/hexanes, two purifications) to give 788 mg (49%) ofintermediate 62c as a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.72-8.75(m, 1H), 8.70 (s, 1H), 8.46 (s, 1H), 7.78-7.84 (m, 1H), 7.31-7.42 (m,2H), 2.42 (s, 3H). Anal. (C₁₁H₉BrN₂) C, H, N.

(d) Intermediate62d—3-[3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-4-methyl-[2,3′]bipyridinyl

The title compound was prepared in 76% yield from intermediate 62b andintermediate 62c similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, DMSO-d₆) δ13.08 (s, 1H), 8.73 (d, 1H, J=4.2 Hz), 8.52-8.57 (m,3H), 7.92-7.98 (m, 2H), 7.68-7.72 (m, 2H), 7.58 (dd, 1H, J=8.7, 1.5 Hz),7.51 (d, 1H, J=7.2Hz), 7.43-7.47 (m, 1H), 7.36 (d, 2H, J=8.7 Hz),7.17-7.23 (m, 2H), 6.91 (d, 2H, J=8.7 Hz), 5.79 (s, 2H), 3.70 (s, 3H),2.21 (s, 3H). Anal. (C₃₃H₂₆N₆O) C, H, N.

(e) Example62—3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-[2,3′]bipyridinyl

Intermediate 62d (400 mg, 9.77 mmol) was stirred in a solution ofconcentrated H₂SO₄ (1 mL) and anisole (1 mL) in TFA (8 mL) for 48 hours.The solution was concentrated to ˜3 mL in vacuo, and was then quenchedwith sat. NaHCO₃ and extracted with 4:1 ethyl acetate/THF. Organics werewashed with brine, dried (MgSO₄), and concentrated in vacuo.Purification by silica gel chromatography (0.2% NH₄OH/6% to 10%MeOH/ethyl acetate) gave 102 mg (33%) of example 62 as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ13.78 (s, 1H), 13.02 (s, 1H), 8.74 (d, 1H, J=4.2Hz), 8.57 (s, 1H), 8.53 (s, 1H), 7.51 (s, 1H), 7.93-7.99 (m, 1H), 7.77(d, 1H, J=8.7 Hz), 7.70 (d, 2H, J=7.8 Hz), 7.43-7.56 (m, 3H), 7.20 (brs, 2H), 2.23 (s, 3H). Anal. (C₂₅H₁₈N₆.0.5H₂O) C, H, N. MS (ES) [m+H]/zcalculated 403, found 403.

EXAMPLE 631-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-3,4-dihydro-2H-[1,7]naphthyridin-1-yl}-ethanone

(a) Intermediate 63a—5-Bromo-1,2,3,4-tetrahydro-[1,7]naphthyridine

Intermediate 54c (1.16 g, 3.08 mmol) was stirred with tetrabutylammoniumfluoride hydrate (2.0 g, 7.65 mmol) in acetonitrile (16 mL) at 72° C.for 18 hours. The solution was allowed to cool and was diluted withethyl acetate. Organics were washed with sat. NaHCO₃ and brine, dried(Na₂SO₄), and concentrated in vacuo. Purification by silica gelchromatography gave 524 mg (80%) of intermediate 63a as a white solid.¹H NMR (300 MHz, CDCl₃) δ7.96 (s, 1H), 7.74 (s, 1H), 4.00 (br s, 1H),3.28-3.33 (m, 2H), 2.74 (q, 2H, J=6.6 Hz), 1.92-2.01 (m, 2H). Anal.(C₈H₉BrN₂) C, H, N.

(b) Intermediate63b—1-(5-Bromo-3,4-dihydro-2H-[1,7]naphthyridin-1-yl)-ethanone

Intermediate 63a (212 mg, 1.0 mmol), DIEA (1.4 mL, 8.0 mmol), and aceticanhydride (4.0 mmol) were stirred in dry chloroform (10 mL) at 68° C.for 40 hours. The solution was washed with saturated NaHCO₃ and brine,dried (Na₂SO₄), and concentrated in vacuo. Purification by silica gelchromatography (70% ethyl acetate/hexanes) gave 242 mg (95%) ofintermediate 63b as a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.61 (br s,1H), 8.46 (s, 1H), 3.79 (q, 2H, J=6.0 Hz), 2.83 (t, 2H, J=6.9 Hz), 2.93(s, 3H), 2.01-2.08 (m, 2H). Anal. (C₁₀H₁₁BrN₂O) C, H, N.

(c) Intermediate63c—1-{5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-3,4-dihydro-2H-[1,7]naphthyridin-1-yl}-ethanone

The title compound was prepared in 83% yield from intermediate 25a andintermediate 63c similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, CDCl₃) δ10.06 (s, 1H), 8.68 (s, 1H), 8.55 (br s, 1H), 8.42 (s,1H), 7.84-7.87 (m, 1H), 7.71 (d, 1H, J=8.7 Hz), 7.50-7.53 (m, 1H), 7.46(dd, 1H, J=8.7, 1.5 Hz), 7.27-7.32 (m, 2H), 5.84 (s, 2H), 3.84 (t, 2H,J=6.6 Hz), 3.64 (t, 2H, J=8.1 Hz), 2.70 (t, 2H), J=6.6 Hz), 2.36 (s,3H), 1.87-1.93 (m, 2H), 0.94 (t, 2H, J=8.1 Hz), −0.04 (s, 9H). Anal.(C₃₀H₃₄N₆O₂Si.0.5H₂O) C, H, N.

(d) Example63—1-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-3,4-dihydro-2H-[1,7]naphthyridin-1-yl}-ethanone

The title compound was prepared in 65% yield by the SEM-deprotection ofintermediate 63c in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.77 (s, 1H), 13.02 (s, 1H), 8.78 (s, 1H),8.46 (br s, 1H), 8.27 (s, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.67 (br.s, 1H),7.49 (dd, 2H, J=5.7, 1.5 Hz), 7.20 (br s, 2H), 3.74 (t, 2H, J=6.3 Hz),2.63 (t, 2H, J=6.3 Hz), 2.27 (s, 3H), 1.79-1.85 (m, 2H). Anal.(C₂₄H₂₀N₆O) C, H, N. MS (ES) [m+H]/z calculated 409, found 409.

EXAMPLE 645-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-nicotinamide

(a) Intermediate 64a—3Bromo-4-methyl-5-carboxamoyl-pyridine

A solution of 3,5-dibromopyridine (3 g, 11.9 mmol) in 150 mL dry THF wascooled to −100° C. (ether-N₂ bath) and BuLi (5 mL of a 2.5 M solution inhexanes, 12.5 mmol) was added dropwise over 3 minutes. After 2additional minutes trimethylsilylisocyanate (3.8 mL of 85% solution,3.24 g, 24 mmol) was added to the yellow anion and the whole was stirredfor 30 minutes at −100° C., 30 minutes at −60° C. and then it wasallowed to reach 25° C. and stirred for 12 hours. The reaction waspoured into saturated aqueous NH₄Cl, extracted with ethyl acetate, theorganic layers were washed with brine, dried (Na₂SO₄), and concentrated.Purification of the residue by chromatography on silica (5:1 to 10:1hexanes-ethyl acetate then 100% ethyl acetate) afforded 236 mg (9%) ofamide 64a. R_(f)=0.09 (50% ethyl acetate in hexanes); ¹H NMR (300 MHz,CDCl₃) δ8.70 (bs, 1H), 8.54 (bs, 1H), 5.98 (bs, 1H), 5.98 (bs, 1H), 5.93(bs, 1H). (LCMS: M⁺215).

(b) Intermediate64b—5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-4-methyl-nicotinamide

The title compound was prepared in 75% yield from intermediate 25a andintermediate 64a similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, CDCl₃) δ10.18 (s, 1H), 8.66 (s, 1H), 8.64 (s, 1H), 8.59 (s,1H), 7.82-7.86 (m, 1H), 7.70 (d, 1H, J=8.4 Hz), 7.48-7.52 (m, 1H), 7.42(dd, 1H, J=8.4, 1.5 Hz), 7.26-7.31 (m, 2H), 6.13 (br s, 1H), 5.91 (br s,1H), 5.83 (s, 2H), 3.64 (t, 2H, J=8.1 Hz), 2.40 (s, 3H), 0.94 (t, 2H,J=8.1 Hz), −0.04 (s, 9H).

(c) Example64—5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4methyl-nicotinamide

The title compound was prepared in 77% yield by the SEM-deprotection ofintermediate 64b in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.80 (s, 1H), 13.03 (s, 1H), 8.54 (s, 1H),8.50 (s, 1H), 8.45 (s, 1H), 8.05 (s, 1H), 7.76 (d, 1H, J=8.7 Hz), 7.68(br.s, 2H), 7.44-7.52 (m, 2H), 7.16-7.22 (m, 2H), 2.29 (s, 3H). Anal.(C₂₁H₁₆N₆O.0.55H₂O) C, H, N. MS (ES) [m+H]/z calculated 369, found 369.

EXAMPLE 653-(1H-Benzoimidazol-2-yl)-5-[5-(1H-imidazolyl-4-yl)-4-methyl-pyridin-3-yl]-1H-indazole

(a) Intermediate 65a—3-Bromo-4-methyl-5-1H-imidazol-4-yl-pyridine

To a stirred suspension of tosylmethyl isocyanide (1.02 g, 5.25 mmol)and 3-bromo-4-methyl-5-formyl pyridine (1.0 g, 5 mmol) in 5 mL of dryethanol was added finely powdered NaCN (25 mg, 0.5 mmol) at 25° C. After30 minutes the reaction was concentrated to an oil. The resulting oilwas added to a saturated solution of ammonia in dry methanol in a sealedtube and heated to 100° C. for 24 hours. Cooling and concentrationfollowed by chromatography on silica (10:1 ethyl acetate-hexanes)afforded 167 mg (14%) of 65a as a white solid. ¹H NMR (300 MHz, DMSO-d₆)δ12.45 (bs, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 7.83 (s, 1H), 7.52 (s, 1H),2.56 (s, 3H).

(b) Intermediate65b—3-Bromo-4-methyl-5-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridine

Intermediate 65a was SEM-protected in 45% yield in a manner analogous tothe procedure for intermediate 49a. ¹H NMR (300 MHz, CDCl₃) δ8.67 (s,1H), 8.60 (s, 1H), 7.70 (s, 1H), 7.21 (d, 1H, J=1.2 Hz), 5.33 (s, 2H),3.56 (t, 2H, J=8.1 Hz), 2.58 (s, 3H), 0.94 (t, 2H, J=8.1 Hz), 0.00 (s,9H). Anal. (C₁₅H₂₂BrN₃OSi) C, H, N.

(c) Intermediate65c—3-(1H-Benzoimidazol-2-yl)-5-{5-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-methyl-pyridin-3-yl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole

The title compound was prepared in 83% yield from intermediate 25a andintermediate 65b similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, CDCl₃) δ10.09 (s, 1H), 8.85 (s, 1H), 7.70 (s, 1H), 8.50 (s,1H), 7.84-7.88 (m, 1H), 7.68-7.74 (m, 2H), 7.47-7.52 (m, 2H), 7.26-7.31(m, 3H), 5.84 (s, 2H), 5.36 (s, 2H), 3.55-3.68 (m, 4H), 2.41 (s, 3H),0.92-0.98 (m, 4H), −0.01 (s, 9H), −0.05 (s, 9H).

(d) Example65—3-(1H-Benzoimidazol-2-yl)-5-[5-(1H-imidazol-4-yl)-4-methyl-pyridin-3-yl]-1H-indazole

The title compound was prepared in 43% yield by the SEM-deprotection ofintermediate 65c in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.78 (s, 1H), 13.02 (s, 1H), 12.38 (s, 1H),8.83 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 7.83 (d, 1H, J=0.9 Hz), 7.76(d, 1H, J=8.4 Hz), 8.69 (d, 1H, J=7.5 Hz), 7.47-7.51 (m, 3H), 7.16-7.22(m, 2H), 2.37 (s, 3H). Anal. (C₂₃H₁₇N₇.2.5H₂O) C, H, N. MS (ES) [m+H]/zcalculated 392, found 392.

EXAMPLE 664-[3-(4,5,6,7-Tetrahydro-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

(a) Intermediate66a—5-Iodo-3-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)-1H-indazole

A solution of intermediate 7b′ (500 mg, 1.24 mmol), 1,2-cyclohexanedione(146 mg, 1.3 mmol), and ammonium acetate (575 mg, 7.44 mmol) in ethanol(12 mL) was stirred at reflux for 4 hours. The reaction was diluted withethyl acetate and washed with brine, dried (Na₂SO₄), and concentrated invacuo. Purification by silica gel chromatography (20% ethylacetate/hexanes) gave 366 mg (60%) of the title compound as a lightyellow foam. ¹H NMR (300 MHz, CDCl₃) δ9.47 (br s, 1H), 8.88 (d, 1H,J=0.9 Hz), 7.69 (dd, 1H, J=8.7, 1.5 Hz), 7.31 (d, 1H, J=8.7 Hz), 5.67(s, 2H), 3.52 (t, 2H, J=8.1 Hz), 2.70 (br s, 4H), 1.89 (br s, 4H), 0.88(t, 2H, J=8.1 Hz), −0.06 (s, 9H). Anal. (C₂₀H₂₇IN₄OSi) C, H, N.

(b) Intermediate66b—4-[3-(4,5,6,7-Tetrahydro-1H-benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-isoquinoline

The title compound was prepared in 75% yield from intermediate 66a andisoquinoline-4-boronic acid (EP 976747) similar to the procedure forintermediate 7d′. ¹H NMR (300 MHz, CDCl₃) δ9.57 (br s, 1H), 9.28 (s,1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.04-8.08 (m, 1H), 7.85-7.89 (s, 1H),7.57-7.70 (m, 4H), 5.80 (s, 2H), 3.63 (t, 2H, J=8.1 Hz), 2.7 (br s, 4H),1.86 (br s, 4H), 0.96 (t, 2H, J=8.1 Hz), −0.03 (s, 9H).

(c) Example66—4-[3-(4,5,6,7-Tetrahydro-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

The title compound was prepared in 64% yield by the SEM-deprotection ofintermediate 66b in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.31 (s, 1H), 12.25 (s, 1H), 9.36 (s, 1H),8.49 (s, 1H), 8.43 (s, 1H), 8.24 (d, 1H, J=7.8 Hz), 7.69-7.85 (m, 4H),7.53 (dd, 1H, J=8.7, 1.8 Hz), 2.50 (br, s, 4H), 1.73 (br s, 4H). Anal.(C₂₃H₁₉N₅.0.2H₂O) C, H, N. MS (ES) [m+H]/z calculated 366, found 366.

EXAMPLE 674-[3-(4-Methyl-5-phenyl-1H-imidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

(a) Intermediate67a—5-Iodo-1-(4-methoxy-benzyl)-3-(4-methyl-5-phenyl-1H-imidazol-2-yl)-1H-indazole

The title compound was prepared from intermediate 19d and1-phenyl-1,2-propanedione similar to the procedure for intermediate 66a.¹H NMR (300 MHz, CDCl₃) δ9.87 (br s, 0.5H), 9.71 (br s, 0.5H), 8.98 (brs, 0.5H), 8.92 (br s, 0.5H), 7.84 (d, 1H, J=7.2 Hz), 7.61 (dd, 1H,J=8.7, 1.5 Hz), 7.44-7.53 (m, 3H), 7.31 (d, 1H, J=7.5 Hz), 7.11 (app d,3H, J=8.7 Hz), 6.81 (dd, 2H, J=6.6, 1.8 Hz), 5.49 (s, 2H), 3.77 (s, 3H),2.55 (s, 3H). Anal. (C₂₅H₂₁IN₄O) C, H, N.

(b) Intermediate67b—4-[1-(4-Methoxy-benzyl)-3-(4-methyl-5-phenyl-1H-imidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

The title compound was prepared in 75% yield from intermediate 67a andisoquinoline-4-boronic acid (EP 976747) in a manner analogous to theprocedure for intermediate 7d′ ¹H NMR (300 MHz, CDCl₃) δ9.97 (br s,0.5H), 9.85 (br s, 0.5H), 9.28 (s, 1H), 8.76 (br s, 0.5H), 8.70 (br s,0.5H), 8.59 (s, 1H), 8.03-8.10 (m, 1H), 7.90 (br s, 1H), 7.75 (br s,1H), 7.37-7.68 (m, 8H), 7.20-7.26 (m, 2H), 6.86 (dd, 2H, J=6.6, 1.5 Hz),5.60 (s, 2H), 3.78 (s, 3H), 2.54 (br s, 1.5H), 2.49 (br s, 1.5H).

(c) Example67—4-[3-(4-Methyl-5-phenyl-1H-imidazol-2-yl)-1H-indazol-5-yl]-isoquinoline

The title compound was prepared in 15% yield by the PMB-deprotection ofintermediate 67b in a manner analogous to the procedure for example 62.¹H NMR (300 MHz, DMSO-d₆) δ12.67 (s, 1H), 13.02 (s, 1H), 9.38 (s, 1H),8.57 (s, 1H), 8.53 (s, 1H), 8.25 (d, 1H, J=7.5 Hz), 7.66-7.91 (m, 6H),7.57 (dd, 1H, J=8.7, 1.5 Hz), 7.30-7.33 (m, 2H), 7.15-7.18 (m, 1H), 2.50(s, 3H). Anal. (C₂₆H₁₉N₅.0.5H₂O) C, H, N. MS (ES) [m+H]/z calculated402, found 402.

EXAMPLE 68Dimethyl-{2-[5-(4-methyl-[3,4′]bipyridinyl-5-yl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-amine

(a) Intermediate68a—{2-[5-Iodo-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-methanol

The title compound was prepared in 40% yield from intermediate 19d andintermediate 23b similar to the procedure for intermediate 7c′. ¹H NMR(300 MHz, DMSO-d₆) δ13.02 (s, 0.5H), 12.87 (s, 0.5H), 8.91 (s, 1H),7.64-7.77 (m, 2.5H), 7.37 (dd, 0.5H, J=7.5, 1.5 Hz), 7.18-7.27 (m, 4H),6.88 (d, 2H, J=8.4 Hz), 5.73 (s, 1H), 5.71 (s, 1H), 5.14-5.24 (m, 1H),5.03 (d, 1H, J=5.7 Hz), 4.86 (d, 1H, J=5.7 Hz), 3.69 (s, 3H).

(b) Intermediate68b—{2-[5-Iodo-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-dimethyl-amine

Intermediate 68a (2.5 g, 4.9 mmol) and DIEA (1.38 mL, 10 mmol) werestirred in THF (90 mL) at 0° C. Methanesulfonyl chloride (0.76 mL, 9.8mmol) was added, and the reaction stirred for 2.5 hours at 0° C.Dimethylamine was bubbled through the solution for 1 minute, and thereaction was allowed to stir for 2 hours while warming to roomtemperature. The solution was quenched with H₂O and extracted with ethylacetate. Organics were washed with sat. NaHCO₃ and brine, dried(Na₂SO₄), and concentrated in vacuo. Purification by silica gelchromatography (0.2% NH₄OH/3% MeOH/ethyl acetate) gave 2.56 g (97%) ofintermediate 68b as a white foam. ¹H NMR (300 MHz, CDCl₃) δ9.07 (d, 1H,J=0.9 Hz), 7.80 (d, 1H, J=7.8 Hz), 7.63 (dd, 1H, J=8.7, 1.5 Hz),7.07-7.25 (m, 5H), 6.85 (dd, 2H, J=6.6, 1.8 Hz), 5.61 (s, 2H), 3.77 (apps, 5H), 2.33 (s, 6H).

(c) Intermediate68c—{2-[1-(4-Methoxy-benzyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-dimethyl-amine

The title compound was prepared in 62% yield from intermediate 68bsimilar to the method for the preparation of intermediate 19e. ¹H NMR(300 MHz, CDCl₃) δ9.11 (s, 1H), 7.82 (dd, 2H, J=8.4, 0.9 Hz), 7.35 (dd,1H, J=8.4, 0.9 Hz), 7.16-7.21 (m, 4H), 6.85 (dd, 2H, J=6.9, 1.8 Hz),5.64 (s, 2H), 3.80 (br s, 2H), 3.76 (s, 3H), 2.35 (s, 6H), 1.37 (s,12H).

(d) Intermediate68d—Dimethyl-{2-[5-(4-methyl-[3,4′]bipyridinyl-5-yl)-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-amine

The title compound was prepared in 85% yield from intermediate 68c andintermediate 53a similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, CDCl₃) δ8.69-8.75 (m, 4H), 8.57 (s, 1H), 8.43 (s, 1H), 7.75(d, 1H, J=8.1 Hz), 7.46 (d, 1H, J=8.7 Hz), 7.34-7.40 (m, 3H), 7.25-7.28(m, 1H), 7.19 (t, 1H, J=7.6 Hz), 7.08 (d, 1H, J=7.2 Hz), 6.89 (d, 2H,J=8.7 Hz), 5.70 (s, 2H), 3.79 (app s, 5H), 2.34 (s, 6H), 2.19 (s, 3H).

(e) Example68—Dimethyl-{2-[5-(4-methyl-[3,4′]bipyridinyl-5-yl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-amine

The title compound was prepared in 20% yield by the PMB-deprotection ofintermediate 68d in a manner analogous to the procedure for example 62.¹H NMR (300 MHz, DMSO-d₆) δ13.80 (s, 1H), 13.01 (s, 1H), 8.71 (dd, 2H,J=4.5, 1.5 Hz), 8.56 (br s, 2H), 8.47 (s, 1H), 7.78 (d, 1H, J=8.7 Hz),7.39-7.58 (m, 4H), 7.17 (br s, 2H), 3.76-3.99 (m, 2H), 2.14-7.29 (m,9H). Anal. (C₂₈H₂₅N₇.1.5H₂O) C, H, N. MS (ES) [m+H]/z calculated 460,found 460.

EXAMPLE 69(3-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-phenyl)-methanol

(a) Intermediate 69a—[3-(5-Bromo-4-methyl-pyridin-3-yl)-phenyl]-methanol

The title compound was prepared in 79% yield from3,5-dibromo-4-methyl-pyridine and 3-(hydroxymethyl)-phenyl-boronic acidsimilar to the procedure for intermediate 53a. ¹H NMR (300 MHz, CDCl₃)δ8.62 (s, 1H), 8.22 (s, 1H), 7.42-7.46 (m, 2H), 7.29 (s, 1H), 7.16-7.20(m, 1H), 4.76 (d, 2H, J=5.7 Hz), 2.48 (t, 1H, J=5.7 Hz), 2.32 (s, 3H).Anal. (C₁₃H₁₂BrNO.0.2H₂O) C, H, N.

(b) Intermediate69b—(3-{5-[3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-phenyl)-methanol

The title compound was prepared in 83% yield from intermediate 62b andintermediate 69a similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, CDCl₃) δ10.39 (s, 1H), 8.69 (s, 1H), 8.45 (s, 1H), 8.36 (s,1H), 7.83-7.87 (m, 1H), 7.36-7.49 (m, 7H), 7.22-7.31 (m, 4H), 6.84 (d,2H, J=8.7 Hz), 5.60 (s, 2H) 4.79 (s, 2H), 3.76 (s, 3H), 2.51 (br s, 1H),2.11 (s, 3H).

(c) Example69—(3-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-phenyl)-methanol

The title compound was prepared in 41 % yield by the PMB-deprotection ofintermediate 69b in a manner analogous to the procedure for example 62.¹H NMR (300 MHz, DMSO-d₆) δ13.79 (s, 1H), 13.02 (s, 1H), 849 (d, 2H,J=6.3 Hz), 8.41 (s, 1H), 7.76 (d, 1H, J=8.7 Hz), 7.34-7.69 (m, 7H),7.19-7.22 (m, 2H), 5.25 (br s, 1H), 4.58 (s, 2H), 2.15 (s, 3H). Anal.(C₂₇H₂₁N₅O₂.1.2H₂O) C, H, N. MS (ES) [m+H]/z calculated 432, found 432.

EXAMPLE 70N-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-methanesulfonamide

(a) Intermediate70a—N-{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-3H-benzoimidazol-5-yl}-methanesulfonamide

The title compound was prepared in 89% yield from intermediate 19f andN-(3,4-diaminophenyl)methanesulfonamide (see Rajappa et al., Indian J.Chem. Sect. B, 19, 7, 1980, 533-535) similar to the procedure forintermediate 7c′. ¹H NMR (300 MHz, MeOD-d₄) δ9.26 (s, 1H), 8.63 (s, 1H),8.49 (s, 1H), 8.20 (d, 1H, J=7.8 Hz), 7.96 (d, 1H, J=7.8 Hz), 7.72-7.81(m, 3H), 7.58-7.63 (m, 3H), 7.35 (d, 2H, J=8.7 Hz), 7.16 (br s, 1H),6.89 (d, 2H, J=8.7 Hz), 5.76 (s, 2H), 3.75 (s, 3H), 2.93 (s, 3H).

(b) Example70—N-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-methanesulfonamide

The title compound was prepared in 48% yield by the PMB-deprotection ofintermediate 70a in a manner analogous to the procedure for example 62.¹H NMR (300 MHz, DMSO-d₆) δ13.83 (s, 1H), 13.04 (s, 1H), 9.54 (br s,1H), 9.40 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.27 (d, 1H, J=8.7 Hz),7.72-7.88 (m, 4H), 7.63 (dd, 1H, J=8.7, 1.5 Hz), 7.54 (br s, 1H), 7.46(s, 1H), 7.07 (d, 1H, J=7.8 Hz), 2.91 (s, 3H). Anal.(C₂₄H₁₈N₆O₂S.1.05H₂O) C, H, N, S. MS (ES) [m+H]/z calculated 455, found455.

EXAMPLE 71N-{2-[5-(4-methyl-[3,4′]bipyridinyl-5-yl)-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-methanesulfonamide

(a) Intermediate71a—1-(4-Methoxy-benzyl)-5-(4-methyl-[3,4′]bipyridinyl-5-yl)-1H-indazole-3-carbaldehyde

The title compound was prepared in 76% yield from intermediate 19e andintermediate 53a similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, CDCl₃) δ10.28 (s, 1H), 8.73 (dd, 2H, J=4.5, 1.5 Hz), 8.49 (s,1H), 8.43 (s, 1H), 8.31 (s, 1H), 7.53 (d, 1H, J=8.7 Hz), 7.40 (dd, 1H,J=8.7, 1.5 Hz), 7.26-7.34 (m, 4H), 6.89 (d, 2H, J=8.7 Hz), 5.67 (s, 2H),3.79 (s, 3H), 2.15 (s, 3H). Anal. (C₂₇H₂₂N₄O₂.0.25H₂O) C, H, N.

(b) Intermediate71b—N-{2-[5-(4-methyl-[3,4′]bipyridinyl-5-yl)-1-(4-methoxy-benzyl)-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-methanesulfonamide

The title compound was prepared in 96% yield from intermediate 71a andN-(3,4-diaminophenyl)methanesulfonamide similar to the procedure forintermediate 7c′. ¹H NMR (300 MHz, MeOD-d₄) δ8.66 (dd, 2H, J=4.5, 1.5Hz), 8.52 (s, 2H), 8.39 (s, 1H), 7.73 (d, 1H, J=8.7 Hz), 7.47-7.65 (m,5H), 7.35 (d, 2H, J=8.7 Hz), 1H), 6.86 (d, 2H, J=8.7 Hz), 5.72 (s, 2H),3.73 (s, 3H), 2.94 (s, 3H), 2.24 (s, 3H).

(c) Example71—N-{2-[5-(4-methyl-[3,4′]bipyridinyl-5-yl)-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-methanesulfonamide

The title compound was prepared in 35% yield by the PMB-deprotection ofintermediate 71b in a manner analogous to the procedure for example 62.¹H NMR (300 MHz, DMSO-d₆) δ13.79 (s, 1H), 13.02 (s, 1H), 9.56 (s, 1H),8.70 (d, 2H, J=5.7 Hz), 8.54 (s, 1H), 8.47 (d, 2H, J=7.8 Hz), 7.78 (d,1H, J=8.7 Hz), 7.49-7.58 (m, 5H), 7.10 (d, 1H, J=8.7 Hz), 2.93 (s, 3H),2.17 (s, 3H). Anal. (C₂₆H₂₁N₇O₂S.1.45 H₂O) C, H, N, S. MS (ES) [m+H]/zcalculated 496, found 496.

EXAMPLE 72{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-methanol

(a) Intermediate 72a—(5-Bromo-4-methyl-pyridin-3-yl)-methanol

Intermediate 59a (1.5 g, 7.5 mmol) was stirred in MeOH at 0° C. Sodiumborohydride (850 mg, 22.5 mmol) was added in portions, and the reactionwas stirred for 1 hour. The solution was diluted with ethyl acetate, andorganics were washed with H₂O and brine, dried (MgSO₄), and concentratedin vacuo. Purification by silica gel chromatography (80% to 100% ethylacetate/hexanes) gave 1.39 g (92%) of intermediate 72a as a white solid.¹H NMR (300 MHz, CDCl₃) δ8.59 (s, 1H), 8.38 (s, 1H), 8.43 (s, 1H), 4.75(d, 1H, J=5.4 Hz), 2.45 (s, 3H), 2.37 (t, 1H, J=5.4 Hz).

(b) Intermediate72b—{5-[3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-methanol

The title compound was prepared in 92% yield from intermediate 62b andintermediate 72a similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, CDCl₃) δ10.48 (s, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 8.42 (s,1H), 7.83 (br s, 1H), 7.45 (d, 2H, J=8.7 Hz), 7.21-7.32 (m, 5H), 6.83(d, 2H, J=8.7 Hz), 5.60 (d, 2H, J=4.5 Hz), 4.80 (s, 2H), 3.76 (s, 3H),2.25 (s, 3H), 1.94 (br s, 1H).

(c) Example72—{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-methanol

The title compound was prepared in 59% yield by the PMB-deprotection ofintermediate 72b in a manner analogous to the procedure for example 62.¹H NMR (300 MHz, DMSO-d₆) δ13.78 (s, 1H), 13.01 (s, 1H), 8.52 (s, 1H),8.43 (s, 1H), 8.39 (s, 1H), 7.75 (dd, 1H, J=8.4, 0.6 Hz), 7.68 (d, 1H,J=7.2 Hz), 7.50 (d, 1H, J=7.2 Hz), 7.44 (dd, 1H, J=8.4, 1.5 Hz),7.15-7.23 (m, 2H), 5.29 (t, 1H, J=5.4 Hz), 4.64 (d, 2H, J=5.4 Hz), 2.22(s, 3H). Anal. (C₂₁H₁₇N₅O.1.25 H₂O) C, H, N. MS (ES) [m+H]/z calculated356, found 356.

EXAMPLE 73{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-dimethyl-amine

(a) Example73—{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-dimethyl-amine

The title compound was prepared in 36% yield from example 72 anddimethylamine by a synthetic method analogous to intermediate 68b. ¹HNMR (300 MHz, DMSO-d₆) δ13.77 (s, 1H), 13.02 (s, 1H), 8.38-8.42 (m, 3H),7.67-7.76 (m, 2H), 7.50 (d, 1H, J=7.8 Hz), 7.44 (dd, 1H, J=8.7, 1.5 Hz),7.14-7.24 (m, 2H), 3.48 (br s, 2H), 2.28 (s, 3H), 2.21 (s, 6H). Anal.(C₂₃H₂₂N₆.0.8 H₂O) C, H, N. MS (ES) [m+H]/z calculated 383, found 383.

EXAMPLE 74{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-ethyl-amine

(a) Example74—{-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-ethyl-amine

The title compound was prepared in 23% yield from example 72 andethylamine by a synthetic method analogous to intermediate 68b. ¹H NMR(300 MHz, DMSO-d₆) δ13.76 (s, 1H), 13.01 (s, 1H), 8.48 (s, 1H), 8.42 (s,1H), 8.36 (s, 1H), 7.74 (d, 1H, J=8.7 Hz), 7.68 (d, 1H, J=7.5 Hz), 7.50(d, 1H, J=7.5 Hz), 7.43 (dd, 1H, J=8.7, 1.5 Hz), 7.14-7.23 (m, 2H), 3.81(s, 2H), 2.65 (q, 2H, J=7.2 Hz), 2.26 (s, 3H), 1.08 (t, 3H, J=7.2 Hz).Anal. (C₂₃H₂₂N₆.0.5 H₂O) C, H, N. MS (ES) [m+H]/z calculated 383, found383.

EXAMPLE 75(3-(1H-Benzoimidazol-2-yl)-5-(4,5-dimethyl-pyridin-3-yl)-1H-indazole

(a) Intermediate 75a—5-Bromo-3,4-dimethyl-pyridine

The title compound was prepared from 3,5-dibromo-4-methyl-pyridine andiodomethane similar to the procedure for intermediate 59a. ¹H NMR (300MHz, CDCl₃) δ8.50 (s, 1H), 8.22 (s, 1H), 2.36 (s, 3H), 2.30 (s, 3H).

(b) Intermediate75b—3-(1H-Benzoimidazol-2-yl)-5-(4,5-dimethyl-pyridin-3-yl)-1-(4-methoxy-benzyl)-1H-indazole

The title compound was prepared in 79% yield from intermediate 62b andintermediate 75a similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, CDCl₃) δ10.66 (s, 1H), 8.64 (s, 1H), 8.40 (s, 1H), 8.36 (s,1H), 7.81-7.85 (m 1H), 7.41-7.49 (m, 2H), 7.18-7.27 (m, 5H), 6.81 (d,2H, J=4.5 Hz), 5.57 (s, 2H), 3.74 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H).

(c) Example75—3-(1H-Benzoimidazol-2-yl)-5-(4,5-dimethyl-pyridin-3-yl)-1H-indazole

The title compound was prepared in 37% yield by the PMB-deprotection ofintermediate 75b in a manner analogous to example 62. ¹H NMR (300 MHz,DMSO-d₆) δ13.76 (s, 1H), 13.02 (s, 1H), 842 (s, 1H), 8.38 (s, 1H), 8.31(s, 1H), 7.74 (dd, 1H, J=8.4, 0.6 Hz), 7.51-7.69 (m, 2H), 7.44 (dd, 1H,J=8.7, 1.8 Hz), 7.17-7.22 (m, 2H) 2.33 (s, 3H), 2.18 (s, 3H). Anal.(C₂₁H₁₇N₅.1.0 H₂O) C, H, N. MS (ES) [m+H]/z calculated 340, found 340.

EXAMPLE 763-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-quinoline

(a) Intermediate76a—3-[3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-4-methyl-quinoline

The title compound was prepared in 86% yield from intermediate 62b and3-bromo-4-methylquinoline (see Kwon et al., Synthesis, 1976, 249)similar to the procedure for intermediate 61c. ¹H NMR (300 MHz, CDCl₃) 810.24 (s, 1H), 8.94 (s, 1H), 8.78 (s, 1H), 8.25 (dd, 1H, J=7.8, 0.3 Hz),8.14 (dd, 1H, J=7.8, 0.3 Hz), 7.75-7.88 (m, 2H), 7.64-7.70 (m, 1H),7.45-7.57 (m, 3H), 7.27-7.35 (m, 4H), 6.91 (d, 2H, J=6.9 Hz), 5.68 (s,2H), 3.82 (s, 3H), 2.70 (s, 3H). Anal. (C₃₂H₂₅N₅O.0.15 C, H, N.

(b) Example76—3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-quinoline

The title compound was prepared in 72% yield by the PMB-deprotection ofintermediate 76a in a manner analogous to the procedure for example 62.¹H NMR (300 MHz, DMSO-d₆) δ13.81 (s, 1H), 13.06 (s, 1H), 8.86 (s, 1H),8.55 (s, 1H), 8.23 (d, 1H, J=7.8 Hz), 8.09 (d, 1H, J=7.2 Hz), 7.68-7.84(m, 3H), 7.55-7.59 (m, 3H), 7.17-7.23 (m, 2H), 2.66 (s, 3H). Anal.(C₂₄H₁₇N₅.0.8 H₂O) C, H, N. MS (ES) [m+H]/z calculated 376, found 376.

EXAMPLE 775-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ol

(a) Intermediate 77a—5-Bromo-4-methyl-pyridin-3-ol

3,5-Dibromo-4-methyl-pyridine (2.42 g, 9.64 mmol) and sodium methoxide(3.12 g, 57.8 mmol) were stirred in a mixture of DMF (8 mL) and MeOH (2mL) in a sealed tube at 180° C. for 24 hours. The reaction was allowedto cool and was concentrated in vacuo. Purification by silica gelchromatography (100% ethyl acetate) gave 1.10 g (61%) of intermediate77a as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.31 (s, 1H), 8.12 (s,1H), 8.04 (s, 1H), 2.21 (s, 3H). Anal. (C₆H₆BrNO) C, H, N.

(b) Intermediate 77b—3-Bromo-5-(4-methoxy-benzyloxy)-4-methyl-pyridine

Intermediate 77a (1.0 g, 5.3 mmol), tetramethylammonium iodide (107 mg,0.53 mmol), and potassium carbonate (1.47 g, 10.6 mmol) were stirred inacetone (30 mL). p-Methoxybenzyl chloride (1.08 mL, 7.98 mmol) wasadded, and the reaction stirred at 55° C. for 8 hours. The solution wasdiluted with ethyl acetate. Organics were washed with H₂O and brine,dried (MgSO₄), and concentrated in vacuo. Purification by silica gelchromatography (25% ethyl acetate/hexanes) gave 648 mg (40%) ofintermediate 77b as a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.33 (s,1H), 8.16 (s, 1H), 7.34 (d, 2H, J=8.7 Hz), 7.93 (d, 2H, J=8.7 Hz), 5.08(s, 2H), 3.83 (s, 3H), 2.34 (s, 3H). Anal. (C₁₄H₁₄BrNO₂) C, H, N.

(c) Intermediate77c—5-[3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ol

The title compound was prepared in 89% yield from intermediate 62b andintermediate 77b similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, CDCl₃) δ10.17 (s, 1H), 8.64 (s, 1H), 8.29 (s, 1H), 8.25 (s,1H), 7.81-7.86 (m, 1H), 7.34-7.49 (m, 5H), 7.21-7.29 (m, 4H), 6.95 (d,2H, J=8.7 Hz), 6.85 (d, 2H, J=8.7 Hz), 5.61 (s, 2H), 5.16 (s, 2H), 3.83(s, 3H), 3.76 (s, 3H), 2.20 (s, 3H).

(d) Example77—5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ol

The title compound was prepared in 47% yield by the PMB-deprotection ofintermediate 77c in a manner analogous to the procedure for example 62.¹H NMR (300 MHz, DMSO-d₆) δ13.74 (s, 1H), 13.01 (s, 1H), 9.91 (s, 1H),8.43 (s, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.72 (dd, 1H, J=8.4, 0.6 Hz),7.69 (bs, 1H), 7.51 (bs, 1H), 7.45 (dd, 1H, J=8.7, 1.5 Hz), 7.17-7.22(m, 2H) 2.09 (s, 3H). Anal. (C₂₀H₁₅N₅O.0.3H₂O) C, H, N. MS (ES) [m+H]/zcalculated 340, found 340.

EXAMPLE 78{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-isopropyl-amine

(a) Example78—{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]methyl-pyridin-3-ylmethyl}-iospropyl-amine

The title compound was prepared in 28% yield from example 72 andisopropylamine using an analogous procedure to the preparation ofintermediate 68b. ¹H NMR (300 MHz, DMSO-d₆) δ13.76 (s, 1H), 13.01 (s,1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 7.74 (d, 1H, J=8.7 Hz),7.68 (d, 1H, J=7.8 Hz), 7.50 (d, 1H, J=7.2 Hz), 7.43 (dd, 1H, J=8.7, 1.5Hz), 7.15-7.25 (m, 2H), 3.79 (s, 2H), 2.80-2.86 (m, 1H), 2.27 (s, 3H),1.07 (d, 6H, J=6.6 Hz). Anal. (C₂₄H₂₄N₆.0.7H₂O C, H, N. MS (ES) [m+H]/zcalculated 397, found 397.

EXAMPLE 79(5-Isoquinolin-4-yl-1H-indazol-3-ylmethylene)-pyrrol-1-yl-amine

(a) Intermediate79a—{5-Isoquinolin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl}1H-indazole-3-carbaldehyde

The title compound was prepared in a manner analogous to the preparationof intermediate 19f, substituting a SEM-protection (see intermediate 3a)for the PMB-protection of intermediate 19c. ¹H NMR (300 MHz, CDCl₃)δ10.30 (s, 1H), 9.30 (s, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.08 (dd, 1H,J=6.6, 2.4 Hz), 7.86 (dd, 1H, J=6.6, 0.6 Hz), 7.81 (dd, 1H, J=8.7, 0.9Hz), 7.64-7.70 (m, 3H), 5.91 (s, 2H), 3.66 (t, 2H, J=8.4 Hz), 0.97 (t,2H, J=8.4 Hz), −0.02 (s, 9H).

(b) Intermediate79b—[5-Isoquinolin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-ylmethylene]-pyrrol-1-yl-amine

Intermediate 79a (400 mg, 0.99 mmol) and 1-aminopyrrole (98 mg, 1.2mmol) were stirred with p-tolunesulfonic acid (10 mg) in toluene (6 mL)at 80° C. for 2 hours. The solution was concentrated in vacuo andpurified by silica gel chromatography (50% ethyl acetate/hexanes) togive 410 mg (89%) of intermediate 79b as a yellow oil. ¹H NMR (300 MHz,CDCl₃) δ9.31 (s, 1H), 8.77 (s, 1H), 8.58-8.60 (m, 2H), 8.09 (dd, 1H,J=7.2, 0.9 Hz), 7.92 (d, 1H, J=7.8 Hz), 7.76 (dd, 1H, J=8.7, 0.9 Hz),7.63-7.70 (m, 3H), 7.19 (t, 2H, J=2.4 Hz), 6.26 (t, 2H, J=2.4 Hz), 5.85(s, 2H), 3.66 (t, 2H, J=8.4 Hz), 0.97 (t, 2H, J=8.4 Hz), −0.02 (s, 9H).

(c) Example79—(5-Isoquinolin-4-yl-1H-indazol-3-ylmethylene)-pyrrol-1-yl-amine

The title compound was prepared in 68% yield by the SEM-deprotection ofintermediate 79b in a manner analogous to the procedure for example 41.¹H NMR (300 MHz, DMSO-d₆) δ13.82 (s, 1H), 9.38 (s, 1H), 9.09 (s, 1H),8.52 (s, 1H), 8.41 (s, 1H), 8.24 (dd, 1H, J=7.2, 1.5 Hz), 7.71-7.85 (m,4H), 7.61 (dd, 1H, J=8.4, 1.5 Hz), 7.46 (t, 2H, J=2.4 Hz), 6.15 (t, 2H,J=2.4 Hz). Anal. (C₂₁H₁₅N₅) C, H, N. MS (ES) [m+H]/z calculated 338,found 338.

EXAMPLE 802-[5-(5-Ethylaminomethyl-4-methyl-pyridin-3-yl)-1H-indazol-3-yl]-1H-benzoimidazole-4-carboxylicAcid Methylamide

(a) Intermediate 80a—(5-Bromo-4-methyl-pyridin-3-ylmethyl)ethyl-amine

The title compound was prepared in 95% yield from intermediate 72a andethylamine using an analogous procedure to the method outlined for thepreparation of intermediate 68b. ¹H NMR (300 MHz, CDCl₃) δ8.59 (s, 1H),8.37 (s, 1H), 3.83 (s, 2H), 2.73 (q, 2H, J=7.2 Hz), 2.48 (s, 3H), 1.16(t, 3H, J=7.2 Hz).

(b) Intermediate 80b—5-Bromo-4-methyl-pyridin-3-ylmethyl)-ethyl-carbamicAcid Dimethyl-ethyl Ester

Intermediate 80a (850 mg, 3.7 mmol) was stirred in a solution of THF (80mL) and 1 N NaOH (10 mL). Di-tert-butyl dicarbonate (1.09 g, 5 mmol) wasadded, and the reaction stirred for 2 hours at room temperature. Thesolution was diluted with ethyl acetate. Organics were washed with H₂Oand brine, dried (MgSO₄), and concentrated in vacuo. Purification bysilica gel chromatography (33% ethyl acetate/hexanes) gave 760 mg (62%)of intermediate 80b as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ8.60 (s,1H), 8.24 (s, 1H), 4.49 (s, 2H), 3.18 (bs, 2H), 2.39 (s, 3H), 1.47 (s,9H), 1.05 (t, 3H, J=7.2 Hz).

(c) Intermediate80c—Ethyl-[5-(3-formyl-1H-indazol-5-yl)-4-methyl-pyridin-3-ylmethyl]carbamicAcid Dimethyl-ethyl Ester

The title compound was prepared in 85% yield from intermediate 19e andintermediate 80b similar to the procedure for intermediate 61c. ¹H NMR(300 MHz, CDCl₃) δ10.27 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 8.23 (s,1H), 7.49 (dd, 1H, J=8.7, 0.6 Hz), 7.26-7.51 (m, 3H), 6.89 (dd, 2H,J=6.6, 2.1 Hz), 5.66 (s, 2H), 4.53 (s, 2H), 3.79 (s, 3H), 3.24 (bs, 2H),2.18 (s, 3H), 1.48 (s, 9H), 1.10 (t, 3H, J=7.2 Hz).

(d) Intermediate80d—Ethyl-{5-[1-(4-methoxy-benzyl)-3-(4-methylcarbamoyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-carbamicAcid Dimethyl-ethyl Ester

The title compound was prepared in 78% yield from intermediate 80c and2-amino-N-methyl-3-nitro-benzamide (Found in: Kania, Braganza, et al.,patent application “Compounds and Pharmaceutical Compositions forInhibiting Protein Kinases, and Methods for Their Use”, p. 52, line 10to p. 53, line 26; and p.59, line 16 to p. 60, line 4, U.S. ProvisionalSerial No. 60/142,130, filed Jul. 2, 1999, incorporated by referenceherein in its entirety.), similar to the procedure for intermediate 7c′.¹H NMR (300 MHz, CDCl₃) δ11.50 (s, 0.3H), 10.21 (s, 0.7H), 9.86 (bs,1H), 8.36-8.57 (m, 3H), 8.18 (dd, 0.7H, J=7.8, 1.2 Hz), 7.97 (dd, 0.3H,J=7.8, 1.2 Hz), 7.63 (dd, 0.7H, J=7.8, 1.2 Hz), 7.24 (m, 5.3H), 6.88 (d,2H, J=6.3 Hz), 5.65 (s, 1.4H), 5.63 (s, 0.6H), 4.57 (bs, 2H), 3.79 (s,3H), 3.27 (bs, 2H), 3.12 (d, 0.9H, J=4.8 Hz), 3.06 (d, 2.1H, J=4.8 Hz),2.29 (s, 2.1H), 2.21 (s, 0.9H), 1.48 (s, 9H), 1.11 (t, 3H, J=6.9 Hz).

(e) Example80—2-[5-(5-Ethylaminomethyl-4-methyl-pyridin-3-yl)-1H-indazol-3-yl]-1H-benzoimidazole-4-carboxylicAcid Methylamide

The title compound was prepared in 36% yield by the PMB-deprotection ofintermediate 80d in a manner analogous to the procedure for example 62,with a final purification by preparatory HPLC (0.1%TFA-ACN/0.1%TFA-H₂O). ¹H NMR (300 MHz, DMSO-d₆) δ14.02 (s, 1H), 13.62(bs, 1H), 9.72 (bs, 1H), 8.88 (bs, 2H), 8.63 (s, 2H), 8.44 (s, 1H),7.83-7.88 (m, 2H), 7.72 (d, 1H, J=7.2 Hz), 7.52 (dd, 1H, J=8.4, 1.5 Hz),7.36 (t, 1H, J=7.8 Hz), 4.33 (bs, 2H), 3.15 (q, 2H, J=7.2 Hz), 2.90 (d,3H, J=4.5 Hz), 2.43 (s, 3H), 1.27 (t, 3H, J=7.2 Hz). Anal. (C₂₅H₂₅N₇O.3TFA) C, H, N. MS (ES) [m+H]/z calculated 440, found 440.

EXAMPLE 81Ethyl-4-{methyl-5-[3-(4-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-pyridin-3-ylmethyl}-amine

(a) Intermediate 81a—3-Methylsulfanyl-2-nitro-phenylamine

3-Chloro-2-nitro-aniline (1.0 g, 5.8 mmol) and potassium carbonate (880mg, 6.4 mmol) were stirred in dry DMF (15 mL) in a sealable tube at 0°C. Methanethiol was bubbled through the solution for 4 minutes. The tubewas sealed and the reaction stirred at 122° C. for 16 hours. The cooledreaction was diluted with H₂O and extracted with ethyl acetate. Organicswere washed with brine, dried (Na₂SO₄), and concentrated in vacuo.Purification by silica gel chromatography (33% ethyl acetate/hexanes)gave 950 mg (89%) of intermediate 81a as a bright red-orange solid. ¹HNMR (300 MHz, CDCl₃) δ7.21 (t, 1H, J=8.1 Hz), 6.55 (d, 2H, J=8.1 Hz),5.93 (bs, 2H), 2.42 (s, 3H). Anal. (C₇H₈N₂O₂S) C, H, N, S.

(b) Intermediate 81b—3-Methylsulfanyl-benzene-1,2-diamine

The title compound was prepared in 96% yield from intermediate 81asimilar to the hydrogenation procedure outlined for intermediate 9a′. ¹HNMR (300 MHz, CDCl₃) δ6.93-6.97 (m, 1H), 6.63-6.70 (m, 2H), 3.71 (bs,4H), 2.36 (s, 3H). Anal. (C₇H₁₀N₂S) C, H, N, S.

(c) Intermediate81c—Ethyl-{5-[1-(4-methoxy-benzyl)-3-(4-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-carbamicAcid Dimethyl-ethyl Ester

The title compound was prepared in 80% yield from intermediate 81b andintermediate 80c similar to the procedure for intermediate 7c′. ¹H NMR(300 MHz, CDCl₃) δ10.15 (s, 0.6H), 10.12 (s, 0.4H), 8.64 (s, 0.4H), 8.59(s, 0.6H), 8.47 (s, 1H), 8.37 (s, 1H), 7.72 (d, 0.6H, J=7.5 Hz), 7.45(t, 1H, J=7.2 Hz), 7.19-7.34 (m, 5H), 7.10 (d, 0.4H, J=7.5 Hz),6.83-6.89 (m, 2H), 5.65 (s, 1.2H), 5.61 (s, 0.8H), 4.55 (bs, 2H), 3.78(s, 1.8H), 3.77 (s, 1.2H), 3.26 (bs, 2H), 2.67 (s, 1.2H), 2.57 (s,1.8H), 2.24 (s, 1.2H), 2.22 (s, 1.8H), 1.49 (s, 9H), 1.12 (t, 3H, J=6.9Hz).

(d) Example81—Ethyl-4{methyl-5-[3(4-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-pyridin-3-ylmethyl}-amine

The title compound was prepared in 25% yield by the PMB-deprotection ofintermediate 81c in a manner analogous to the procedure for example 62.¹H NMR (300 MHz, DMSO-d₆) δ13.78 (s, 1H), 13.10 (s, 1H), 8.48 (s, 1H),8.44 (s, 1H), 8.39 (s, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.44 (d, 1H, J=8.7,1.8 Hz), 7.30 (d, 1H, J=7.8 Hz), 7.19 (t, 1H, J=7.8 Hz), 6.99 (d, 1H,J=7.2 Hz), 3.82 (s, 2H), 2.66 (q, 2H, J=7.2 Hz), 2.56 (s, 3H), 2.28 (s,3H), 1.08 (t, 3H, J=7.2 Hz). Anal. (C₂₄H₂₄N₆S.1.5H₂O), C, H, N, S. MS(ES) [m+]/z calculated 429, found 429.

EXAMPLE 82N-{2-[5-(5-Ethylaminomethylmethyl-pyridin-3-yl)-1H-indazol-3-yl]-1H-benzoimidazol4-yl}acetamide

(a) Intermediate 82a—N-(2,3-diamino-phenyl)-acetamide

The title compound was prepared in 98% yield fromN-(2-amino-3-nitro-phenyl)-acetamide (see Harvey et al., J. Chem. Soc.Perk. Trans. 1, 1988, 1939-1944) in a manner analogous to thehydrogenation of intermediate 9a′. ¹H NMR (300 MHz, CDCl₃) δ9.04 (s,1H), 6.35-6.49 (m, 3H), 4.38 (bs, 4H), 2.00 (s, 3H).

(b) Intermediate82b—{5-[3-(4-Acetylamino-1H-benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-ethyl-carbamicAcid Dimethyl-ethyl Ester

The title compound was prepared in 65% yield from intermediate 82a andintermediate 80c similar to the procedure for intermediate 7c′. ¹H NMR(300 MHz, CDCl₃) δ12.35 (bs, 1H), 10.80 (bs, 1H), 7.90-8.85 (m, 4H),6.76-7.46 (m, 8H), 5.60 (bs, 2H), 4.51 (bs, 2H), 3.78 (s, 3H), 3.61 (bs,2H), 3.19 (bs, 3H), 1.74 (bs, 12H), 1.18 (bs, 3H). MS (ES) [m+H]/zcalculated 660, found 660.

(c) Example82—N-{2-[5-(5-Ethylaminomethyl-4-methyl-pyridin-3-yl)-1H-indazol-3-yl]-1H-benzoimidazol-4-yl}-acetamide

The title compound was prepared in 6% yield by the PMB-deprotection ofintermediate 82b in a manner analogous to the procedure for example 62.¹H NMR (300 MHz, MeOD-d₄) δ8.64 (s, 1H), 8.58 (s, 1H), 8.45 (s, 1H),7.82 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=7.2 Hz), 7.50 (d, 2H, J=7.2 Hz),7.34 (t, 1H, J=8.4 Hz), 4.44 (s, 2H), 3.27 (q, 2H, J=7.5 Hz), 2.43 (s,3H), 2.22 (s, 3H), 1.41 (t, 3H, J=7.5 Hz). MS (ES) [m+H]/z calculated440, found 440.

EXAMPLE 83 5-(2,6-Difluorophenyl)-3-Phenyl-1H-indazole

(a) Intermediate 83a—5-(2,6-Difluorophenyl)-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

By a synthetic method analogous to intermediate 11e, palladium catalyzedcoupling of intermediate 11d with 2,6-difluorophenylboronic acid yielded83a (65%) as a pale yellow foam: ¹H NMR (DMSO-d₆) δ−0.09 (s, 9H), 0.84(t, 2H, J=8.0 Hz), 3.62 (t, 2H, J=8.0 Hz), 5.86 (s, 2H), 7.24 (dd, 2H,J=8.1, 8.3 Hz), 7.44 (tt, 1H, J=1.3, 7.2 Hz), 7.47-7.58 (m, 4H), 7.92(dd, 1H, J=0.5, 8.8 Hz), 7.98 (dd, 2H, J=1.3, 8.2 Hz), 8.14(d, 1H, J=0.5Hz).

(a) Example 83—5-(2,6-Difluorophenyl)-3-phenyl-1H-indazole

Similar to example 7′, treatment of 83a with tetrabutylammonium fluorideafforded 5-(2,6-difluorophenyl)-3-phenyl-1H-indazole 83 (95%) as ayellow solid:: ¹H NMR (DMSO-d₆) δ7.23 (dd, 2H, J=8.1, 8.3 Hz), 7.40 (tt,1H, J=1.3, 7.2 Hz), 7.43-7.56 (m, 4H), 7.70 (dd, 1H, J=0.6, 8.7 Hz),7.98 (dd, 2H, J=1.3, 8.4 Hz), 8.11 (d, 1H, J=0.6 Hz), 13.38 (s, 1H).Anal. (C₁₉H₁₂N₂F₂) C, H, N.

EXAMPLE 84 5-Amino-3(2-Pyrrolyl)-1H-indazole

By a synthetic method analogous to intermediate 18c, hydrogenation of5-nitro-3-(2-pyrrolyl)-1H-indazole 18b′ over 10% palladium on carbonafforded 5-amino-3-(2-pyrrolyl)-1H-indazole 84 (99%) as a beige solid:¹H NMR (DMSO-d₆) δ6.13 (dd, 1H, J=2.4, 2.6 Hz), 6.49 (dd, 1H, J=1.5, 2.4Hz), 6.76 (dd, 1H, J=1.5, 2.6 Hz), 6.79 (dd, 1H, J=2.1, 8.9 Hz), 7.03(d, 1H, J=2.1 Hz), 7.22 (d, 1H, J=8.9 Hz), 11.16 (s, 1H), 12.45 (s, 1H).Anal. (C₁₁H₁₀N₄.0.2 ethyl acetate) C, H, N.

EXAMPLE 85 5-(Benzylamino)-3-(2-Pyrrolyl)-1H-indazole

Benzaldehyde (100 mg, 1 mmol) was added to a solution of5-amino-3-(2-pyrrolyl)-1H-indazole 84 (100 mg, 0.5 mmol) in EtOH (100ml). The resultant solution was stirred for 2 hours at ambienttemperature prior to addition of NaBH₃CN (50 mg, 0.8 mmol) in a singleportion as the solid. After stirring for an additional 2 hours, thecrude reaction mixture was poured into H₂O (200 ml) and extracted withethyl acetate (2×100 ml). The combined organic extracts were dried oversodium sulfate and concentrated. Silica gel chromatography (60% ethylacetate/hexanes) provided 85 (21%) as a beige solid: ¹H NMR (DMSO-d₆)δ4.33 (s, 2H), 6.11 (dd, 1H, J=2.5, 2.6 Hz), 6.38 (dd, 1H, J=1.5, 2.5Hz), 6.74 (dd, 1H, J=1.5, 2.6 Hz), 6.81 (s, 1H), 6.91 (dd, 1H, J=1.9,8.9 Hz), 7.17-7.36 (m, 5H), 7.43 (d, 1H, J=8.9 Hz), 7.45 (d, 1H, J=1.9Hz), 11.13 (s, 1H), 12.48 (s, 1H). Anal. (C₁₈H₁₆N₄.0.33H₂O) C, H, N.

EXAMPLE 86 5-(3-Methoxyphenyl)-3-(phenyl)-1H-indazole

(a) Intermediate86a—5-(3-Methoxyphenyl)-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole

By a synthetic method to intermediate 11e, palladium catalyzed couplingof intermediate 11d with 3-methoxyphenylboronic acid yielded 86a (46%)as a pale yellow solid: ¹H NMR (DMSO-d₆) δ−0.10 (s, 9H), 0.84 (t, 2H,J=8.0 Hz), 3.62 (t, 2H, J=8.0 Hz), 5.86 (s, 2H), 7.24-7.34 (m, 4H),7.38-7.56 (m, 4H), 7.84(d, 1H, J=8.3 Hz), 7.91-8.03 (m, 3H).

(b) Example 86—5-(3-Methoxyphenyl)-3-phenyl-1H-indazole

Similar to example 11, treatment of 86a with tetrabutylammonium fluorideafforded 5-(3-methoxyphenyl)-3-phenyl-1H-indazole 86 (71%) as a whitesolid:: ¹H NMR (DMSO-d₆) δ3.83 (s, 3H), 6.93 (dd, 1H, J=1.9, 8.0 Hz),7.22-7.75 (m, 8H), 8.04 (dd, 2H, J=1.3, 7.2 Hz), 8.20 (d, 1H, J=0.3 Hz),13.27(s, 1H). Anal. (C₂₀H₁₆N₂O.0.2H₂O) C, H, N.

EXAMPLE 87{5-[3-(1H-Benzoimidazol-2-yl)-H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-isobutyl-amine

(a) Example87—{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-isobutyl-amine

The title compound was prepared in 81% yield from example 72 andisobutylamine using an analogous procedure to the preparation ofintermediate 68b. ¹H NMR (300 MHz, DMSO-d₆) δ13.77 (s, 1H), 13.02 (s,1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.37 (8, 1H), 7.74 (d, 1H, J=8.7 Hz),7.68 (d, 1H, J=7.5 Hz), 7.50 (d, 1H, J=7.5 Hz), 7.43 (dd, 1H, J=8.7, 1.5Hz), 7.14-7.24 (m, 2H), 3.85 (s, 2H), 2.49 (bs, 2H), 2.27 (s, 3H),1.73-1.79 (m, 1H), 0.90 (d, 6H, J=6.6 Hz). Anal. (C₂₅H₂₆N₆.0.3H₂O) C, H,N. MS (ES) [m+H]/z calculated 411, found 411.

EXAMPLE 88{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-benzyl-amine

(a) Example88—{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}benzyl-amine

The title compound was prepared in 73% yield from example 72 andbenzylamine similar to intermediate 68b. ¹H NMR (300 MHz, DMSO-d₆)δ13.77 (s, 1H), 13.02 (s, 1H), 8.51 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H),7.74 (d, 1H, J=8.7 Hz), 7.68 (d, 1H, J=7.5 Hz), 7.50 (d, 1H, J=7.5 Hz),7.16-7.44 (m, 8H), 3.90 (bs, 4H), 2.23 (s, 3H). Anal. (C₂₈H₂₄N₆.1.2H₂O)C, H, N. MS (ES) [m+H]/z calculated 445, found 445.

EXAMPLE 892-({5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-amino)-ethanol

(a) Example89—2-({5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-amino)-ethanol

The title compound was prepared in 54% yield from example 72 andethanolamine similar to intermediate 68b. ¹H NMR (300 MHz, DMSO-d₆)δ13.78 (s, 1H), 13.01 (s, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.42 (s, 1H),7.75 (d, 1H, J=8.7 Hz), 7.67 (d, 1H, J=7.5 Hz), 7.51 (d, 1H, J=7.5 Hz),7.43 (dd, 1H, J=8.7, 1.5 Hz), 7.15-7.23 (m, 2H), 4.82 (bs, 1H), 4.03 (s,2H), 3.60 (d, 2H, J=2.7 Hz), 2.87 (t, 2H, J=2.7 Hz), 2.29 (s, 3H). Anal.(C₂₃H₂₂N₆O.0.1H₂O) C, H, N. MS (ES) [m+H]/z calculated 399, found 399.

EXAMPLE 90 {1-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-ethyl}methyl-amine

(a) Intermediate 90a—N-(2-Acetyl-6nitro-phenyl)-acetamide

A solution of 2,3-dimethyl-7-nitroindole (Acros Organics, 13.55 g, 71.24mmol) in dichloromethane (1.0 L) was cooled to −60° C. internaltemperature and treated with ozone gas for 1.5 hours. A color changefrom orange to yellow-green was observed in this time. Argon was bubbledthrough the solution for one hour, causing the color to change toyellow. Dimethylsulfide (10.5 mL, 142.5 mmol) was added, and stirringcontinued at −60° C. for 1.5 hours. After warming to room temperature,the solution was concentrated in vacuo to ˜200 mL, washed with water(2×50 mL), dried over magnesium sulfate, filtered, concentrated, andpurified by silica gel chromatography (50 to 100% ethyl acetate inhexanes), affording 90a (11.85 g, 75%) as an orange solid. R_(f)=0.36(75% ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) δ2.02 (s, 3H), 2.52 (s,3H), 7.52 (t, 1H, J=7.9 Hz), 8.00 (dd 1H, J=7.9, 1.5 Hz), 8.05 (dd, 1H,J=8.1, 1.5 Hz),10.32 (s, 1H). Anal. (C₁₀H₁₀N₂O₄.0.4 H₂O) C, H, N.

(b) Intermediate 90b—1-(2-Amino-3-nitro-phenyl)-ethanone

Concentrated hydrochloric acid (40 mL) was added to a solution of 90a(4.00 g, 18.0 mmol) in absolute ethanol (80 mL) and water (40 mL). Themixture was heated to reflux (87° C. internal temperature) for 1 hour.After cooling to room temperature, saturated aqueous sodium bicarbonatesolution was added to bring the pH to 8. The solution was extracted withethyl acetate (2×200 mL). The combined organic extracts were dried overmagnesium sulfate, filtered, concentrated and purified by silica gelchromatography (20 to 70% ethyl acetate in hexanes) to give 90b (2.67 g,82%) as a yellow solid. R_(f)=0.45 (50% ethyl acetate/hexanes); ¹H NMR(DMSO-d₆) δ2.62 (s, 3H), 6.74 (t, 1H, J=8.1 Hz), 8.31 (m. 2H), 8.85 (brs, 2H). Anal. (C₈H₈N₂O₃) C, H, N.

(c) Intermediate 90c—1-(2,3-Diamino-phenyl)-ethanone

By a synthetic method analogous to the synthesis of 9a, hydrogenation of90b (2.00 g, 11.1 mmol) in ethanol afforded 90c (1.54 g, 92%) as brightyellow crystals. R_(f)=0.34 (50% ethyl acetate/hexanes); ¹H NMR(DMSO-d₆) δ6 2.47 (s, 3H), 4.75 (br s, 2H), 6.40 (dd, 1H, J=7.5, 8.1Hz), 6.69 (dd, 1H, J=7.5, 1.3 Hz), 6.79 (br s, 2H), 7.10 (dd, 1H, J=8.1,1.3 Hz). Anal. (C₈H₁₀N₂O) C, H, N.

(d) Intermediate90d—1-{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-yl}-ethanone

Similar to the synthesis of 19h, aldehyde 19t (2.02 g, 5.13 mmol) anddiamine 90c (771 mg, 5.13 mmol) were condensed in the presence of sulfurto give 90d (1.83 g, 68%) as a bright yellow solid. R_(f)=0.19 (75%ethyl acetate/hexanes); ¹H NMR (DMSO-d₆) [Some peaks are doubled due totautomeric isomerization] δ2.72 and 2.87 (2 br s, 3H together), 3.71 (s,3H), 5.85 (s, 2H), 6.93 (d, 2H, J=8.7 Hz), 7.34 (m, 3H), 7.75 (m, 5H),8.07 (m, 2H), 8.25 (d, 1H, J=7.5 Hz), 8.56 and 8.80 (2 br s, 2Htogether), 9.38 (s, 1H), 11.83 (s, 1H), 13.53 (s, 1H).

(e) Intermediate90e—(1-{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-yl}-ethyl)-methyl-amine

A solution of methylamine in methanol (2.0 M, 3.02 mL, 6.04 mmol) wasadded to ketone 90d (527.8 mg, 1.01 mmol) at room temperature, followedby hydrochloric acid (4.0 mL in dioxane, 0.504 mL, 2.02 mmol), methanol(6.0 mL), and sodium cyanoborohydride (38.0 mg, 0.605 mmol). Thesuspension was stirred at room temperature for 23 hours, but no reactionwas observed by TLC analysis. Anhydrous THF (10 mL) was added toincrease solubility, and stirring continued for 70 hours. The mixturewas partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate solution. The organic phase was dried over magnesiumsulfate, filtered, concentrated and purified by silica gelchromatography (1:20:200 aq. NH₄OH:ethanol:dichloromethane), yielding90e (275.0 mg, 51%) as a yellow foam. R_(f)=0.09 (1:20:400 aqueousNH₄OH:ethanol:dichloromethane); ¹H NMR (CD₃OD) δ1.53 (d, 3H, J=6.8 Hz),2.24 (s, 3H), 3.75 (s, 3H), 4.28 (q, 1H, J=6.8 Hz), 5.45 (s, 1H),5.77(s, 2H), 6.89 (d, 2H, J=8.7 Hz), 7.22 (m, 2H), 7.34 (d, 2H, J=8.7Hz), 7.52 (d, 1H, J=7.9 Hz),7.61 (dd, 1H, J=8.7, 1.5 Hz), 7.76 (m, 3H),7.99 (d, 1H, J=8.3 Hz), 8.20 (dd, 1H, J=7.2, 1.7 Hz), 8.48 (s, 1H), 8.70(s, 1H), 9.27 (s, 1H). Anal. (C₃₄H₃₀N₆O.1.0 H₂O) C, H, N.

(f) Example90—{1-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-ethyl}-methyl-amine

A solution of 90e (179.7 mg, 0.334 mmol), trifluoromethanesulfonic acid(0.84 mL), and trifluoroacetic acid (3.34 mL) was stirred at 50° C. for2 hours. The solution was then added dropwise to a rapidly stirredmixture of concentrated aqueous NH₄OH (10 mL) and ethyl acetate (30 mL).Extraction and purification similar to example 33, afforded 90 as anoff-white solid (140.9 mg). Although this material appeared pure by HPLCand ¹H NMR analysis, the elemental analysis showed significantimpurities. The impure material was dissolved in ethyl acetate (50 mL)and washed with water (10 mL), saturated aqueous sodium bicarbonatesolution (10 mL), and saturated aqueous sodium chloride solution (10mL). The organic layer was dried over magnesium sulfate, filtered andconcentrated to give 90 (49.4 mg, 35%) as a white solid: ¹H NMR (CD₃OD)δ1.71 (d, 3H, J=6.8 Hz), 2.45 (s, 3H), 4.66 (q, 1H, J=7.0 Hz), 7.24 (d,1H, J=7.5 Hz), 7.32 (t, 1H, J=7.7 Hz), 7.61 (dd, 1H, J=7.9, 1.0 Hz),7.67(dd, 1H, J=8.5, 1.5 Hz), 7.82 (m, 3H), 8.03 (d, 1H, J=8.3 Hz), 8.24 (d,1H, J=7.5 Hz), 8.53 (s, 1H), 8.71 (s, 1H), 9.30 (s, 1H). Anal.(C₂₆H₂₂N₆.0.4 CH₂Cl₂) C, H, N.

EXAMPLE 913-(1H-Benzoimidazol-2-yl)-5-(4-methyl-5-morpholin-4-ylmethyl-pyridin-3-yl)-1H-indazole

(a) Example91—3-(1H-Benzoimidazol-2-yl)-5-(4-methyl-5-morpholin-4-ylmethyl-pyridin-3-yl)-1H-indazole

The title compound was prepared in 68% yield from example 72 andmorpholine using an analogous procedure to the preparation ofintermediate 68b. ¹H NMR (300 MHz, DMSO-d₆) δ13.78 (s, 1H), 13.02 (s, 1H), 8.42 (s, 2H), 8.40 (s, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.59 (br s, 2H),7.44 (dd, 1H, J=8.7, 1.5 Hz), 7.17-7.22 (m, 2H), 3.58-3.67 (m, 6H), 2.48(br s, 4H), 2.30 (s, 3H). Anal. (C₂₅H₂₄N₆O.0.7 H₂O) C, H, N. MS (ES)[m+H]/z calculated 425, found 425.

EXAMPLE 92{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-cyclopentyl-amine

(a) Example92—{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-cyclopentyl-amine

The title compound was prepared in 49% yield from example 72 andcyclopentylamine using an analogous procedure to the preparation ofintermediate 68b. ¹H NMR (300 MHz, MeOD-d₄) δ8.49 (s, 1H), 8.46 (s, 1H),8.42 (s, 1H), 7.73 (d, 1H, J=8.7 Hz), 7.64 (br s, 2H), 7.45 (d, 1H,J=8.7 Hz), 7.24-7.28 (m, 2H), 3.95 (s, 2H), 3.25 (br s, 1H), 2.39 (s,3H) 1.96-2.02 (m, 2H), 1.71-1.78 (m, 2H), 1.46-1.67 (m, 4H). Anal.(C₂₆H₂₆N₆.0.25 H₂O) C, H, N. MS (ES) [m+H]/z calc'd 423, found 423.

EXAMPLE 93{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-pyridin-3-yl-amine

(a) Example93—{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4methyl-pyridin-3-ylmethyl}-pyridin-3-yl-amine

The title compound was prepared in 10% yield from example 72 and3-amino-pyridine using an analogous procedure to the preparation ofintermediate 68b. ¹H NMR (300 MHz, DMSO-d₆) δ13.79 (s, 1H), 13.03 (s,1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.42 (s, 1H), 8.09 (s, 1H), 7.83 (s,1H), 7.75 (d, 1H, J=8.7 Hz), 7.59 (br s, 2H), 7.45 (d, 1H, J=8.7 Hz),7.09-7.22 (m, 4H), 6.55 (br s, 1H), 4.40 (d, 1H, J=6.0 Hz), 2.28 (s,3H). Anal. (C₂₆H₂₁N₇.0.5 H₂O) C, H, N. MS (ES) [m+H]/z calc'd 432, found432.

Biochemical and Biological Evaluation

Cyclin-dependent kinase activity was measured by quantifying theenzyme-catalyzed, time-dependent incorporation of radioactive phosphatefrom [³²P]ATP or [³³P]ATP into a protein substrate. Unless notedotherwise, assays were performed in 96-well plates in a total volume of50 μL, in the presence of 10 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]) (pH 7.4), 10mM MgCl₂, 25 μM adenosine triphosphate (ATP), 1 mg/mL ovalbumin, 5 μg/mLleupeptin, 1 mM dithiothreitol, 10 mM beta-glycerophosphate, 0.1 mMsodium vanadate, 1 mM sodium fluoride, 2.5 mM ethyleneglycol-bis(β-aminoethyl ethKer)-N,N,N′N′-tetraacetic acid (EGTA), 2%(v/v) dimethylsulfoxide, and 0.03-0.4 μCi [^(32/33)P]ATP per reaction.Reactions were initiated with appropriate enzyme, incubated at 30° C.,and terminated after 20 minutes by the addition ofethylenediaminetetraacetic acid (EDTA) to 250 mM. The phosphorylatedsubstrate was then captured on a nitrocellulose or phosphocellulosemembrane using a 96-well filtration manifold, and unincorporatedradioactivity was removed by repeated washing with 0.85% phosphoricacid. Radioactivity was quantified by exposing the dried membranes to aphosphorimager.

Apparent K_(i) values were measured by assaying enzyme activity in thepresence of different inhibitor compound concentrations and subtractingthe background radioactivity measured in the absence of enzyme.Inhibition data were fit to an equation for competitive inhibition usingKaleidagraph (Synergy Software), or were fit to an equation forcompetitive tight-binding inhibition using the software KineTic (BioKin,Ltd.).

Inhibition of CDK4/Cyclin D Retinoblastoma Kinase Activity

A complex of human CDK4 and cyclin D3, or a complex of human CDK4 andgenetically truncated (1-264) cyclin D3, was purified using traditionalbiochemical chromatographic techniques from insect cells that had beenco-infected with the corresponding baculovirus expression vectors (seee.g., Meijer and Kim, “Chemical Inhibitors of Cyclin-Dependent Kinases,”Methods in Enzymol,. vol. 283 (1997), pp. 113-128.). The enzyme complex(5 or 50 nM) was assayed with 0.3-0.5 μg of purified recombinantretinoblastoma protein fragment (Rb) as a substrate. The engineered Rbfragment (residues 386-928 of the native retinoblastoma protein; 62.3kDa) contains the majority of the phosphorylation sites found in thenative 106-kDa protein, as well as a tag of six histidine residues forease of purification. Phosphorylated Rb substrate was captured bymicrofiltration on a nitrocellulose membrane and quantified using aphosphorimager as described above. For measurement of tight-bindinginhibitors, the enzyme complex concentration was lowered to 5 nM, andthe assay duration was extended to 60 minutes, during which thetime-dependence of product formation was linear.

Inhibition of CDK2/Cyclin A Retinoblastoma Kinase Activity

CDK2 was purified using published methodology (Rosenblatt et al.,“Purification and Crystallization of Human Cyclin-dependent Kinase 2,”J. Mol. Biol., vol. 230, 1993, pp. 1317-1319) from insect cells that hadbeen infected with a baculovirus expression vector. Cyclin A waspurified from E. coli cells expressing full-length recombinant cyclin A,and a truncated cyclin A construct was generated by limited proteolysisand purified as described previously (Jeffrey et al., “Mechanism of CDKactivation revealed by the structure of a cyclin A-CDK2 complex,”Nature, vol. 376 (Jul. 27, 1995), pp. 313-320). A complex of CDK2 andproteolyzed cyclin A was prepared and purified by gel filtration. Thesubstrate for this assay was the same Rb substrate fragment used for theCDK4 assays, and the methodology of the CDK2/cyclin A and theCDK4/cyclin D3 assays was essentially the same, except that CDK2 waspresent at 150 nM or 5 nM. K_(i) values were measured as describedabove.

The stimulation of cell proliferation by growth factors such as VEGF andothers is dependent upon their induction of autophosphorylation of eachof their respective receptor's tyrosine kinases. Therefore, the abilityof a protein kinase inhibitor to block cellular proliferation induced bythese growth factors is directly correlated with its ability to blockreceptor autophosphorylation. To measure the protein kinase inhibitionactivity of the compounds, the following constructs were used.

VEGF-R2 Construct for Assay

This construct determines the ability of a test compound to inhibittyrosine kinase activity. A construct (VEGF-R2Δ50) of the cytosolicdomain of human vascular endothelial growth factor receptor 2 (VEGF-R2)lacking the 50 central residues of the 68 residues of the kinase insertdomain was expressed in a baculovirus/insect cell system. Of the 1356residues of full-length VEGF-R2, VEGF-R2Δ50 contains residues 806-939and 990-1171, and also one point mutation (E990V) within the kinaseinsert domain relative to wild-type VEGF-R2. Autophosphorylation of thepurified construct was performed by incubation of the enzyme at aconcentration of 4 μM in the presence of 3 mM ATP and 40 mM MgCl₂ in 100mM Hepes, pH 7.5, containing 5% glycerol and 5 mM DTT, at 4° C. for 2hours After autophosphorylation, this construct has been shown topossess catalytic activity essentially equivalent to the wild-typeautophosphorylated kinase domain construct. See Parast et al.,Biochemistry, 37,16788-16801 (1998).

CHK1 Construct for Assay

C-terminally His-tagged full-length human CHK1 (FL-CHK1) was expressedusing the baculovirus/insect cell system. It contains 6 histidineresidues (6×His-tag) at the C-terminus of the 476 amino acid human CHK1.The protein was purified by conventional chromatographic techniques.

VEGF-R2 Assay Coupled Spectrophotometric (FLVK-P) Assay

The production of ADP from ATP that accompanies phosphoryl transfer wascoupled to oxidation of NADH using phosphoenolpyruvate (PEP) and asystem having pyruvate kinase (PK) and lactic dehydrogenase (LDH). Theoxidation of NADH was monitored by following the decrease of absorbanceat 340 nm (e₃₄₀=6.22 cm⁻¹ mM⁻¹) using a Beckman DU 650spectrophotometer. Assay conditions for phosphorylated VEGF-R2Δ50(indicated as FLVK-P in the tables below) were the following: 1 mM PEP;250 μM NADH; 50 units of LDH/mL; 20 units of PK/mL; 5 mM DTT; 5.1 mMpoly(E₄Y₁); 1 mM ATP; and 25 mM MgCl₂ in 200 mM Hepes, pH 7.5. Assayconditions for unphosphorylated VEGF-R2Δ50 (indicated as FLVK in thetables) were the following: 1 mM PEP; 250 μM NADH; 50 units of LDH/mL;20 units of PK/mL; 5 mM DTT; 20 mM poly(E₄Y₁); 3 mM ATP; and 60 mM MgCl₂and 2 mM MnCl₂ in 200 mM Hepes, pH 7.5. Assays were initiated with 5 to40 nM of enzyme. K_(i) values were determined by measuring enzymeactivity in the presence of varying concentrations of test compounds.The data were analyzed using Enzyme Kinetic and Kaleidagraph software.

ELISA Assay

Formation of phosphogastrin was monitored using biotinylated gastrinpeptide (1-17) as substrate. Biotinylated phosphogastrin was immobilizedusing streptavidin coated 96-well microtiter plates followed bydetection using anti-phosphotyrosine-antibody conjugated to horseradishperoxidase. The activity of horseradish peroxidase was monitored using2,2′-azino-di-[3-ethylbenzathiazoline sulfonate(6)] diammonium salt(ABTS). Typical assay solutions contained: 2 μM biotinylated gastrinpeptide; 5 mM DTT; 20 μM ATP; 26 mM MgCl₂; and 2 mM MnCl₂ in 200 mMHepes, pH 7.5. The assay was initiated with 0.8 nM of phosphorylatedVEGF-R2Δ50. Horseradish peroxidase activity was assayed using ABTS, 10mM. The horseradish peroxidase reaction was quenched by addition of acid(H₂SO₄), followed by absorbance reading at 405 nm. K_(i) values weredetermined by measuring enzyme activity in the presence of varyingconcentrations of test compounds. The data were analyzed using EnzymeKinetic and Kaleidagraph software.

CHK1 Assay

The production of ADP from ATP that accompanies phosphoryl transfer tothe synthetic substrate peptide Syntide-2 (PLARTLSVAGLPGKK) was coupledto oxidation of NADH using phosphoenolpyruvate (PEP) through the actionsof pyruvate kinase (PK) and lactic dehydrogenase (LDH). The oxidation ofNADH was monitored by following the decrease of absorbance at 340 nm(ε340=6.22 cm⁻¹ mM⁻¹) using a HP8452 spectrophotometer. Typical reactionsolutions contained: 4 mN PEP; 0.15 mM NADH; 28 units of LDH/ml; 16units of PK/ml; 3 mM DTT; 0.125 mM Syntide-2; 0.15 mM ATP; 25 mM MgCl₂in 50 mM TRIS, pH 7.5; and 400 mM NaCl. Assays were initiated with 10 nMof FL-CHK1. K_(i) values were determined by measuring initial enzymeactivity in the presence of varying concentrations of test compounds.The data were analyzed using Enzyme Kinetic and Kaleidagraph software.

Inhibition of Phosphorylated FGF Receptor and LCK Tyrosine KinaseActivity

Cloning, expression and purification of the cytosolic domain of FGFR1tyrosine kinase (amino acids 456-766) containing three amino acidsubstitutions (L457V, C488A, and C584S) were conducted as previouslydescribed (Mohammadi, M., Schlessinger, J., & Hubbard, S. R. (1996) Cell86, 577-587). This domain was expressed in Sf9 insect cells using abaculovirus expression vector, and protein was purified usingconventional techniques. The LCK tyrosine kinase was expressed in insectcells as an N-terminal deletion starting from amino acid 223 to the endof the protein at amino acid 509. The N-terminus of the protein also hadtwo amino acid substitutions, P223M and C 224D. Kinases were purifiedusing conventional chromatographic methods.

Tyrosine kinase activity was measured using a coupled, continuousspectrophotometric assay, in which production of phosphorylatedpoly(Glu, Tyr; 4:1) substrate and ADP is coupled to the pyruvatekinase-catalyzed transfer of a phosphate from phosphoenolpyruvate toADP, with generation of pyruvate and regeneration of ATP. Pyruvateproduction is in turn coupled to the lactate dehydrogenase-catalyzedreduction of pyruvate to form lactate, with concomitant conversion ofNADH to NAD⁺. Loss of NADH is monitored by measuring absorbance at 340nm (see e.g., Technikova-Dobrova et al., “Spectrophotometricdetermination of functional characteristics of protein kinases withcoupled enzymatic assay,” FEBS Letters, vol. 292 (1991), pp. 69-72).Enzyme activity was measured in the presence of 200 mM HEPES (pH 7.5), 2mM phosphoenolpyruvate, 0.3 mM NADH, 20 mM MgCl₂, 100 μM ATP, 5 mM DTT,5.1 or 25 mM poly (Glu, Tyr) 4:1 for P-FGF or P-LCK assays,respectively, and 15 units/mL each of pyruvate kinase and lactatedehydrogenase. Phosphorylated FGF receptor kinase was present at 100 nMand phosphorylated LCK kinase was present at 50 nM. Assays wereperformed under initial rate conditions at 37° C., and rates werecorrected for any background rate measured in the absence of enzyme.Percent inhibition was calculated relative to control enzyme assayed inthe presence of 2% (v/v) DMSO. The results are shown in Table 1.

Coupled Spectrophotometric (FAK) Assay

Tyrosine kinase assays were monitored using a Beckman DU 650Spectrophotometer. Production of ADP was coupled to oxidation of NADHusing phosphoenolpyruvate (PEP) through the actions of pyruvate kinase(PK) and lactic dehydrogenase (LDH). The oxidation of NADH was monitoredby following the decrease in absorbance at 340 nm (ε₃₄₀=6.22 cm⁻¹ mM⁻¹).Typical reaction solutions contained: 1 mM PEP, 250 μM NADH, 50 units ofLDH/mL, 20 units of PK/mL, 5 mM DTT, in 200 mM Hepes, pH 7.5 and varyingconcentrations of poly(E₄Y₁), ATP and MgCl₂. Assays were initiated with40 nM of cdFGFR1.

Results of assays performed on compounds, which include the specificexamples described above are provided below in Table I. Unless indicatedotherwise in a particular entry, the units and assays used are asindicated in the applicable column of the table.

TABLE I K_(i) with Kinases K_(i) K_(i) K_(i) VEGF LCK K_(i) CHK1 (μM)(μM) FGF (μM) K_(i) K_(i) (μM) or % or % or % FAK % CDK4/D CDK2/A or %Inhib. at 1 Inhib. at Inhib. at Inhibition Ex. No. (μM) (μM) Inhib. μM 1μM 1 μM at 1 μM 1 1.7 ± 11 ± 6.7 ± NT NT NT 32 0.6 2 0.09 2 7.9 ± NT NTNT NT NT NT 3.0 3 0.37 ± 0.24 ± 75% NT NT NT NT 0.05 0.01 inhibition at20 μM 4 0.11 ± 0.14 ± 1.09 ± 0.0264 ± NT NT NT 0.02 0.01 0.12 0.002 50.48 ± 0.69 ± 56% NT NT NT NT 0.04 0.03 at 20 μM 6 0.2 ± 0.16 ± 80% 64%11% 53% NT 0.03 0.02 at 20 μM 7′ 1.2 ± 0.79 ± NT NT NT NT NT 0.3 0.12 8′0.59 ± 0.37 ± NT NT NT NT NT 0.10 0.04 9′ 2.2 ± 0.67 ± NT NT NT NT NT0.3 0.07 10′ 0.074 ± 0.033 ± 5% NT 21% 61% NT 0.009 0.003 inhibition @10 μM 11 39% 2.6 ± NT NT NT NT NT inhibition 0.3 at 10 μM 11a 48% 13 NTNT NT NT NT inhibition at 100 μM 12 19% 6.3 ± NT NT NT NT NT inhibition1.1 at 5 μM 13 3.4 ± 2.7 ± NT NT NT NT NT 0.7 0.7 14 2.4 ± 2.5 ± NT NTNT NT NT 0.5 0.4 14b 20% NT NT NT NT NT NT inhibition at 1 μM 15′ 0.0180.062 ± 16% NT 17% 87% NT 0.007 inhibition at 1 μM 16 0.035 0.015 81 36%NT 1 47% 17 NT 1.4 NT NT NT 42.6% NT 18 0.96 NT NT NT NT NT NT 18b′ 6.63.3 NT NT NT NT NT 19 0.054 0.001 NT NT NT 31.3% NT inhibition 20 0.00210.00093 NT NT NT 96.9% NT 21 0.237 0.049 8.55 NT 23% 54% NT 22 0.0150.094 NT NT NT 93.5% NT 23 0.065 0.041 NT NT NT 0.8 NT 24 0.69 1.1 NT NTNT 45.4% NT 25 0.01 0.001 NT NT NT 0.44 NT 26 0.083 0.072 NT NT NT NT NT27 1.5 1.6 NT NT NT NT 44% 28 0.68 0.72 NT NT NT NT 61% 29 0.00770.00047 NT 6% NT 2.2 NT 30 0.011 0.001 NT NT NT 52.4% NT 31 0.000370.00021 NT 2.9; 17% NT 55.5% NT 32 0.00041 0.00025 NT NT NT 29.7% NT 330.0011 0.001 NT NT NT 51.6% NT 34 0.019 0.001 NT NT NT 26.9% NT 350.0032 0.001 NT NT NT 40.5% NT 36 0.0023 0.001 NT 15% NT 55.8% NT 370.00076 0.00022 NT 17% NT 34.4% NT 38 0.000798 0.001 NT 9% NT 42.4% NT39 0.009 0.0011 NT NT NT NT NT 40 0.0022 0.00038 NT NT NT NT NT 41 0.0780.25 NT NT NT NT NT 42 0.0082 0.0172 NT NT NT 70.3% 78% 43 0.015 0.029NT NT NT 59.6% NT 44 0.019 0.029 NT NT NT 56.2% NT 45 0.012 0.017 NT NTNT 58.7% 63% 46 0.03 0.028 NT 51% NT 50.5% NT 47 0.094 0.1 NT NT NT81.1% NT 48 0.021 0.055 7.82 NT NT 68.5% NT 49 0.095 0.049 NT NT NT86.7% NT 50 0.253 0.073 NT NT NT 89.6% NT 51 1.1 0.4 NT NT NT NT NT 520.0035 0.0026 NT 38% NT 55% NT 53 0.0026 0.00029 NT 32% NT 32% NT 540.026 0.00027 NT 46% NT 81.5% ± 55 0.041 0.0011 NT 32% NT 83.6% NT 560.036 0.001 NT NT NT NT NT 57 0.65 0.037 NT NT NT NT NT 58 0.0067 0.001NT 17% NT 3; 20.3% NT 59 0.0016 0.00058 NT 31% NT 47.6% NT 60 0.00160.0006 NT 26% NT 40.8% NT 61 0.017 0.0012 NT 18% NT 0.48; NT 60.7% 620.05 0.0037 NT NT NT NT NT 63 0.22 0.0012 NT NT NT NT NT 64 0.19 0.014NT NT NT NT NT 65 0.0028 0.001 NT NT NT 44.1% NT 66 0.055 0.001 NT NT NTNT NT 67 0.22 0.016 NT NT NT NT NT 68 0.0047 0.0011 NT NT NT 12.6% NT 690.015 0.0041 NT 38% NT 25.6% NT 70 0.0018 0.00023 NT 45% NT 63% NT 710.00085 0.001 NT 42% NT 28.8% NT 72 0.012 0.0076 NT 24% NT 48.6% NT 730.0069 0.0027 NT 15% NT 42.9 NT 74 0.00052 0.0016 NT 14% NT 82.6 NT 750.0098 0.0014 NT NT NT NT NT 76 0.15 0.027 NT NT NT NT NT 77 0.00580.00038 NT NT NT NT NT 78 0.0055 0.0007 NT NT NT NT NT 79 0.0022 0.00042NT NT NT NT NT 80 0.014 0.00025 NT NT NT NT NT 81 0.0008 0.0049 NT NT NTNT NT 82 0.11 0.0024 NT NT NT NT NT 83 30% at 30% at NT NT NT NT NT 10μM 10 μM 84 34 28 22.5 NT NT NT NT 85 16 6.6 NT NT NT NT NT 86 18% at45% at NT NT NT NT NT 10 μM 10 μM 87 0.0042 0.0019 NT NT NT NT NT 880.0035 0.0014 NT NT NT NT NT 89 0.001 0.00094 NT NT NT NT NT 90 0.000090.0003 NT NT NT NT NT 91 0.0075 0.0028 NT NT NT NT NT 92 0.0078 0.0027NT NT NT NT NT 93 0.0019 0.00061 NT NT NT NT NT Note: NT = not tested.

Inhibition of Cell Growth: Assessment of Cytotoxicity

Inhibition of cell growth was measured using the tetrazolium salt assay,which is based on the ability of viable cells to reduce3-(4,5-dimethylthiazol-2-yl)-2,5-[2H]-diphenyltetrazolium bromide (MTT)to formazan (Mossman, Journal of Immunological Methods, vol. 65 (1983),pp. 55-58). The water-insoluble purple formazan product was thendetected spectrophotometrically. The HCT 116 cell line was grown in96-well plates. Cells were plated in the appropriate medium at a volumeof 135 μl/well in McCoy's 5A Medium. Plates were incubated for fourhours before addition of inhibitor compounds. Different concentrationsof inhibitor compounds were added in 0.5% (v/v) dimethylsulfoxide (15μL/well), and cells were incubated at 37° C. (5% CO₂) for four to sixdays (depending on cell type). At the end of the incubation, MTT wasadded to a final concentration of 0.2 mg/mL, and cells were incubatedfor 4 hours more at 37° C. After centrifugation of the plates andremoval of medium, the absorbance of the formazan (solubilized indimethylsulfoxide) was measured at 540 nm. concentration of inhibitorcompound causing 50% inhibition of growth was determined from the linearportion of a semi-log plot of inhibitor concentration versus percentageinhibition. All results were compared to control cells treated only with0.5% (v/v) dimethylsulfoxide.

TABLE II HCT116 HCT116 Example No. IC50 (uM) IC90 (uM) 4 2.7 6.2 6 6 2110 1.5 3.8 15 1.2 2.5 16 3 5 17 3.2 5 19 0.78 1.6 20 0.07 0.4 22 5 5 234 5 25 0.33 1.1 26 2.8 5 29 0.18 0.8 30 0.18 0.62 31 0.22 0.058 32 0.0860.23 33 0.055 0.16 34 0.2 0.58 35 0.13 0.37 36 0.024 0.06 37 0.041 0.1238 0.029 0.06 39 0.018 0.06 42 3 5 43 1.9 5 44 5 5 45 2.1 5 47 2.1 5 483.9 5 49 2.3 4.8 50 1.8 5 52 0.5 2.2 53 0.2 0.75 54 0.079 0.23 55 1.5 556 0.48 1.3 57 2 5 58 0.46 1.3 59 0.2 0.48 60 0.2 0.5 61 0.22 0.5 62 12.4 63 0.43 1.3 64 1.3 5 65 0.39 1.3 66 0.49 1.6 61 2 4.7 68 0.16 0.6 690.69 2.1 70 0.18 0.44 71 0.7 2 72 0.15 0.53 73 0.2 0.6 75 0.4 1.3 76 0.50.5 77 0.31 0.5 78 0.085 0.22 79 0.5 0.5 80 0.09 0.22 81 0.086 0.2182 >0.5 >0.5 87 0.16 0.42 88 >0.5 >0.5 89 0.15 0.25 90 0.03 0.12 910.34 >0.5 92 0.18 0.5 93 0.32 >0.5

The examples above illustrate compounds according to Formula I or II andassays that may readily be performed to determine their activity levelsagainst the various kinase complexed. It will be apparent that suchassays or other suitable asssays known in the art may be used to selectan inhibitor having a desired level of activity against a selectedtarget.

The exemplary compounds described above may be formulated intopharmaceutical compositions according to the following general examples.

Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula I or II is dissolved in DMSO and then mixed with 10mL of 0.9% sterile saline. The mixture is incorporated into a dosageunit form suitable for administration by injection.

Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula I or II is mixed with 750 mg of lactose. The mixtureis incorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

It is to be understood that the foregoing description is exemplary andexplanatory in nature, and is intended to illustrate the invention andits preferred embodiments. Thus, the scope of the invention should beunderstood to be defined not by the foregoing description, but by thefollowing claims and their equivalents.

What is claimed is:
 1. A compound represented by Formula I:

wherein R₁ is a substituted or unsubstituted aryl, a heteroarylcontaining 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, ora heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; and R₂ is a substituted or unsubstituted aryl,a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; or a pharmaceutically acceptable salt of acompound of the Formula I; or a prodrug or pharmaceutically activemetabolite of a compound of the Formula I, or a pharmaceuticallyacceptable salt of a prodrug or metabolite thereof.
 2. A compound,pharmaceutically acceptable salt, prodrug, or pharmaceutically activemetabolite according to claim 1, wherein: R₁ is

wherein R₄ is hydrogen; or

wherein Y is CH or N and R₃ is H, or a substituted or unsubstitutedalkyl, aryl, carbocycle, heteroaryl, or heterocycle group; or

where Y is C or N and R₃ is H or a substituted or unsubstituted alkyl,aryl, heteroaryl, carbocycle, or heterocycle group.
 3. A compoundselected from the group consisting of

or a pharmaceutically acceptable salt thereof, a prodrug orpharmaceutically active metabolite thereof, or a pharmaceuticallyacceptable salt of a prodrug or metabolite thereof.
 4. A pharmaceuticalcomposition comprising: (a) an amount of a cell-cycle control agenteffective to inhibit a protein kinase, said cell-cycle control agentbeing a compound represented by Formula I:

wherein R₁ is hydrogen or a substituted or unsubstituted aryl, aheteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; and R₂ is a substituted or unsubstituted aryl,a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedaryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; or a pharmaceutically acceptable salt of acompound of the Formula I; or a prodrug or pharmaceutically activemetabolite of a compound of the Formula I, or a pharmaceuticallyacceptable salt of a prodrug o)r metabolite thereof; and apharmaceutically acceptable carrier.
 5. A method of treating a diseaseor disorder mediated by inhibition of a kinase complex, comprisingadministering to a subject in need of such treatment an effective amountof a cell-cycle control agent selected from the group consisting of acompound represented by Formula I:

wherein R₁ is a substituted or unsubstituted aryl, a heteroarylcontaining 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, aheterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; and R₂ is a substituted or unsubstituted aryl,a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; or a pharmaceutically acceptable salt of acompound of the Formula I; or a prodrug, or pharmaceutically activemetabolite of a compound of the Formula I, or a pharmaceuticallyacceptable salt of a prodrug or metabolite thereof.
 6. A pharmaceuticalcomposition comprising: (a) a therapeutically effective amount of acompound represented by Formula I:

wherein R₁ is hydrogen or a substituted or unsubstituted aryl, aheteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; and R₂ is a substituted or unsubstituted aryl,a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedaryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms, or a pharmaceutically acceptable salt of acompound of the Formula I; or a prodrug or pharmaceutically activemetabolite of a compound of the Formula I, or a pharmaceuticallyacceptable salt of a prodrug or metabolite thereof; and (b) apharmaceutically acceptable carrier, diluent, vehicle or excipienttherefor.
 7. A method of treating a mammalian disease condition mediatedby kinase activity, comprising administering to a mammal in need thereofa therapeutically effective amount of a compound represented by FormulaI:

wherein R₁ is hydrogen or a substituted or unsubstituted alkyl, aryl, aheteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; and R₂ is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedaryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; or a pharmaceutically acceptable salt of acompound of the Formula I; or a prodrug or pharmaceutically activemetabolite of a compound of the Formula I, or a pharmaceuticallyacceptable salt of a prodrug or metabolite thereof.
 8. A methodaccording to claim 7, wherein the mammalian disease condition isassociated with tumor growth, cell proliferation, or angiogensis.
 9. Amethod of modulating or inhibiting the activity of a protein kinasereceptor, comprising contacting the receptor with an effective amount ofa compound represented by the Formula I:

wherein R₁ is hydrogen or a substituted or unsubstituted alkyl, aryl, aheteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; and R₂ is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedaryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; or a pharmaceutically acceptable salt of acompound of the Formula I; or a prodrug or pharmaceutically activemetabolite of a compound of the Formula I, or a pharmaceuticallyacceptable salt of a prodrug or metabolite thereof.
 10. A methodaccording to claim 9, wherein the protein kinase receptor is a CDKcomplex, VEGF, or CHK1.
 11. A pharmaceutical composition, comprising aneffective amount for inhibiting a kinase complex of a cell-cycle controlagent, represented by Formula I:

wherein R₁ is hydrogen or a substituted or unsubstituted aryl, aheteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; and R₂ is a substituted or unsubstituted aryl,a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedaryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; or a pharmaceutically acceptable salt of acompound of the Formula I; or a prodrug or pharmaceutically activemetabolite of a compound of the Formula I, or a pharmaceuticallyacceptable salt of a prodrug or metabolite thereof.
 12. A method oftreating a disease state or disorder associated with uncontrolledcellular proliferation comprising administering to a subject in needthereof a therapeutically effective amount of a compound represented byFormula I:

wherein R₁ is hydrogen or a substituted or unsubstituted alkyl, aryl, aheteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, or

wherein R₄ is H or lower alkyl, and X is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; and R₂ is a substituted or unsubstitutedalkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms, or

wherein R₄ is H or lower allyl, and X is a substituted or unsubstitutedaryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogenheteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms; or a pharmaceutically acceptable salt of acompound of the Formula I; or a prodrug or pharmaceutically activemetabolite of a compound of the Formula I, or a pharmaceuticallyacceptable salt of a prodrug or metabolite thereof.
 13. A compoundrepresented by Formula II

wherein R′₁ is a substituted or unsubstituted aryl, a heteroarylcontaining 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, ora heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms or

wherein each R₄ is individually H or lower alkyl, and X is a substitutedor unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atomsand 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing5-10 ring atoms and 1-3 nitrogen heteroatoms; and R′₂ is a substitutedor unsubstituted amino, nitro, alkenyl, aryl, a heteroaryl containing5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, a heterocyclecontaining 5-10 ring atoms and 1-3 nitrogen heteroatoms,

wherein the R₄ groups are independently H or lower alkyl, and X is asubstituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocyclecontaining 5-10 ring atoms and 1-3 nitrogen heteroatoms; or apharmaceutically acceptable salt of a compound of the Formula II; or aprodrug or pharmaceutically active metabolite of a compound of theFormula II, or a pharmaceutically acceptable salt of the prodrug ormetabolite thereof.
 14. A compound, pharmaceutically acceptable salt,prodrug, or pharmaceutically active metabolite thereof according toclaim 13, wherein R′₁ is

wherein Y is independently CH, CR₃ or N and the R₃ groups areindependently one or more of H, substituted or unsubstituted alkyl,alkenyl, aryl, carbocycle, heteroaryl, heterocycle, hydroxy, halogen,alkoxy, aryloxy, heteroaryloxy, thioaryl, thioheteroaryl, thioalkyl,thioacyl, or amino, provided that there can be more than one R₃ group.15. A compound according to claim 14, wherein R′₂ is a substituted orunsubstituted nitrogen-containing heteroaryl and R′₁ is


16. A compound according to claim 13, wherein R₂′ comprises asubstituted or unsubstituted heterocycle containing 5-10 ring atoms and1-3 nitrogen heteroatoms.
 17. A compound according to claim 13, whereinR′₂ comprises a substituted or unsubstituted group of the formula


18. A compound according to claim 13, wherein R′₂ comprises asubstituted or unsubstituted or unsubstituted group of the formula


19. A compound according to claim 13, wherein R′₂ comprises asubstituted or unsubstituted group of the formula


20. A compound according to claim 14, wherein R′₂ comprises asubstituted or unsubstituted group of the formula


21. A compound according to claim 13, wherein R′₂ comprises asubstituted or unsubstituted group of the formula


22. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof, a prodrug orpharmaceutically active metabolite thereof, or a pharmaceuticallyacceptable salt of a prodrug or metabolite thereof.
 23. A pharmaceuticalcomposition for treating a disease state associated with uncontrolledcellular proliferation comprising: i. an effective amount of a compoundas claimed in claim 13 or a pharmaceutically acceptable salt, prodrug orpharmaceutically active metabolite or a pharmaceutically acceptable saltof a metabolite or prodrug thereof, and ii. a pharmaceuticallyacceptable carrier.
 24. A method of treating a disease state or disorderassociated with uncontrolled cellular proliferation comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound represented by Formula II:

wherein R′₁ is a substituted or unsubstituted alkyl, aryl, a heteroarylcontaining 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, ora heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms or

wherein each R₄ is individually H or lower alkyl, and X is a substitutedor unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atomsand 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing5-10 ring atoms and 1-3 nitrogen heteroatoms; and R′₂ is a substitutedor unsubstituted amino, nitro, alkenyl, alkyl, aryl, a heteroarylcontaining 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, aheterocycle

 containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, wherein the R₄groups are independently H or lower alkyl, and X is a substituted orunsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10ring atoms and 1-3 nitrogen heteroatoms; or a pharmaceuticallyacceptable salt of a compound of the Formula II; or a prodrug orpharmaceutically active metabolite of a compound of the Formula II, or apharmaceutically acceptable salt of the prodrug or metabolite thereof.25. A compound according to claim 1, wherein R₁ is

and wherein R₂ is


26. A compound according to claim 13, wherein R′₁ is

and wherein R′₂ is